TEDDI: radiotherapy delivery in deep inspiration for pediatric patients − a NOPHO feasibility study

Long-term survival following childhood cancer is excellent, with 5-year overall survival rates exceeding 80% [1, 2]. It is, however, thoroughly documented that childhood cancer survivors suffer from a treatment-induced excess mortality and morbidity when compared to the general population or siblings [3‐5].

Radiotherapy (RT) is known to induce late effects in childhood cancer survivors; primarily cardiovascular disease and second cancers [5‐10]. Due to the long latency period, radiation-induced late effects are difficult to assess and quantify as they are often the consequence of treatment regimens now considered outdated. Nonetheless, the risk of radiation-induced late effects is known to be influenced by both the radiation dose and the volume of irradiated tissue [7, 11‐13].

In modern RT, advanced imaging, highly conformal treatment planning and delivery techniques, as well as respiratory motion management systems have been introduced in the adult setting in order to reduce the radiation to healthy organs at risk (OARs) surrounding the treatment target. Deep inspiration breath-hold (DIBH) is a simple technique where the irradiation is delivered only while the patient holds his/her breath. A breath-hold in deep inspiration causes a change in patient anatomy (i.e. inflation of the lungs, rotation and elongation of the heart) and imaging artifacts from respiratory movement are diminished. The technique significantly reduces the radiation dose to the surrounding OARs, without compromising the delivered radiation dose to the treatment target, and with no detriment to other healthy organs [14‐17]. The OAR dose reduction is estimated to reduce the risk of late effects [18]. Consequently, DIBH is widely used across the world for adult patients with left-sided breast cancer and mediastinal lymphoma.

However, the experience with DIBH in the pediatric setting is sparse [19, 20]. In general there has been a reluctance to implement new RT techniques in the pediatric setting as late effects data are not available with these new techniques. Regarding motion management systems an additional concern has been the skepticism about children’s compliance with breathing instructions.

With TEDDI we will introduce radiotherapy delivery in deep-inspiration for pediatric patients within a multicenter setting through the NOPHO (Nordic Society of Pediatric Haematology and Oncology) network; accommodating the need for systematic research of RT delivery techniques in pediatric patients.

The dosimetric benefit from RT in DIBH has been well documented in the adult setting [14‐17], however respiratory motion management is not routinely used in the pediatric setting.

TEDDI is the first formalized study to introduce RT delivery in DIBH for pediatric patients.

Prior to clinical implementation of TEDDI, a pilot study was conducted at Rigshospitalet in order to investigate whether children from the age of five are able to perform stable and reproducible DIBHs using the RPM system. To assess the patient compliance qualitatively, the participating children and families completed a questionnaire after the DIBH training session. The questionnaire evaluated the child’s comfort with the pre-training information and the DIBH coaching. Based on experiences gained from this pilot study a standard operating procedure for RT delivery in DIBH for pediatric patients has been developed.

Two prior studies have described the experience with DIBH in pediatric patients [19, 20]. Both studies used a spirometry-assisted breath-hold technique. Claude et al. [19] concluded that only older children are able to comply and understand the technique, and it increases the estimated daily treatment time at the linac. Spirometry-assisted DIBH has in adults been reported less comfortable than the optical surface tracking DIBH approach [26], employed in TEDDI. Our DIBH-method is performed as a non-invasive procedure and constitutes a very gentle treatment expected to cause a minimal inconvenience to this fragile patient population. When treating very young children, however, prolonged treatment time at the linac might be unavoidable.

Recently Huijskens et al. investigated the respiratory-induced motion of the diaphragm and the intra- and interfractional variability in children during image-guided RT [27]. They found a large range of the diaphragm amplitude motion, mean 10.7 mm (range 4.1–17.4 mm), with the intrafractional variability being the largest. Because of the substantial patient variability they concluded that a 4DCT in children should be performed to quantify the individual respiratory motion in order to define individual safety margins. TEDDI will clarify whether RT in DIBH can reduce this variability, potentially allowing for smaller margins and, thus, a reduced dose to the OARs.

DIBH seems to be compatible with proton therapy, however, data and availability is still limited. The experience gained from TEDDI will be directly transferable to proton treatment facilities. Also, DIBH holds the potential for synergistic combinations with other new RT principles, e.g. dose painting with a boost to radio-resistant areas of the tumor, as this technique requires that tumor motion is minimal in order to deliver the radiation dose correctly.

In conclusion, RT in DIBH is a promising technique in a pediatric setting, which could have a dramatic impact on the risk of late effects following RT for childhood cancer, improving subsequent quality of life, morbidity, and - ultimately - mortality.