30. Paediatric malignancies - The GEC-ESTRO Handbook of Brachytherapy

Paediatric malignancies

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/09/2023

treatment quality, and possibly minimizing the risk of long-term side effects. Historically, Iridium-192 wires were widely used for interstitial BT procedures in the paediatric population [25]. Since Iridium192 wires are no longer commercially available in most parts of the word, there has been a shift from LDR to either pulsed-dose rate BT (PDR) or high-dose rate (HDR) BT. Due to a theoretical superiority, PDR treatments are preferred, if possible, to minimize the risk of long-term normal tissue complication. An increasing number of recent publications however suggests that HDR treatments can also be delivered with good results, although the number of patients treated is still low. The vast majority of paediatric tumours that can be treated with BT are soft tissue sarcoma, mainly represented by rhabdomyosarcoma (RMS) and the ongoing European Paediatric Soft tissue sarcoma Study Group (EpSSG) FAR-RMS protocol has included a description on BT techniques and indications (clinicalTrial.gov reference NCT04625907). RMS are the most frequent paediatric soft tissue tumours, accounting for 4-6 % of all paediatric cancers. The main indications for BT are tumours arising in the gynaecological, urological, or head and neck area. Tumours of the limbs or the trunk are also good indications for BT, usually as peri-operative treatments. Prior to the 1990’s, there was a high incidence of gynaecological clear cell carcinoma related to post intrauterine diethylstilbestrol exposure and numerous clinical data show the place of BT in this situation, alone or in combination with surgery or external radiotherapy [27, 31]. Since the use of diethylstilbestrol has stopped, these tumours have become excessively rare and are not discussed here. BT may be also indicated in non-sarcoma tumours (ex: rare squamous cell carcinoma or adenocarcinoma, germ cell tumours), alone or in combination with external irradiation and/or surgery. Indications are the same as in adults, though technical aspects of paediatric treatments should be considered, because of obvious differences in organ dimensions. This chapter focusses on the place and treatment modalities for BT in paediatric RMS. For tumour sites suitable for BT, the anatomy and topography of tumours of children are usually comparable to those in adults. However, the dimensions of organs are obviously smaller. This must be considered at time of implant and at time of treatment planning. There is a large amount of clinical data showing that irradiated and treated volume is a major factor in developing complications. Such relationship between these volumes and the risk of long-term treatment-related morbidity was shown in paediatric tumours, especially for vaginal tumours treated with BT [27]. In addition, RMS are usually very large tumours at diagnosis, and therefore relationships between the target volume and the organs at risk may be closer than in adults. There are variations in frequency of the primary sites of the tumours related to the age of the patients. For example, vaginal rhabdomyosarcoma is seen during early childhood, while RMS of the uterine cervix are more frequently seen in teenagers. In the head and neck area there is typically a distinction between 3. ANATOMICAL TOPOGRAPHY

tumours arising from the orbit, non-parameningeal tumours and parameningeal tumours. Important in this regard is the difference in prognosis between these different sites. Parameningeal tumours are those located in the nasopharynx, nasal cavity, parapharyngeal area, paranasal sinuses, infratemporal and pterygopalatine fossa, middle ear, and mastoid. Non-parameningeal tumours are for example located in the oral cavity, ear, cheek, scalp, salivary glands, and neck.

4. PATHOLOGY

RMS are classified into embryonal subtype RMS (~80% of all rhabdomyosarcomas) or alveolar RMS (15-20% of all RMS). Other RMS subtypes are rare in children and adolescents. Alveolar rhabdomyosarcomas exhibit a poorer prognosis. Botryoid sarcoma is a variant form of embryonal RMS, mainly seen in gynaecological, bladder and urinary tract RMS. Embryonal and alveolar RMS show distinct molecular patterns and biology. Thus, balanced chromosomal translocations resulting in PAX3/FOXO1 and PAX7/FOXO1 fusion genes are evidenced in more than 80% of alveolar RMS. The outcome of patients with fusion-gene negative alveolar RMS seems to be like the one for patients with embryonal RMS [57, 69]. Soft tissue sarcoma other than RMS are rare (e.g., synovial sarcoma, extra-osseous Ewing and Ewing-like sarcoma, malignant peripheral nerve sheath tumour, fibrosarcoma, alveolar soft part sarcoma). Though few data are available for BT in these tumour types, mainly based on case reports, these are potential indications for BT and should be discussed on a case per case basis, considering tumour site, the possibility of alternative conservative treatments, technical feasibility of BT, and tumour volume. Various risk factors for paediatric soft tissue sarcoma have been identified. Those are mainly from inherited disorders and include: Li-Fraumeni syndrome, DICER1 syndrome (for gynaecological RMS), RB1 gene changes, neurofibromatosis type 1, SMARCB1 gene changes, intrauterine diethylstilbestrol exposure and a history of radiation exposure. When there is a syndrome associated with a high risk of second cancers (e.g., Li-Fraumeni syndrome), local treatments without irradiation should be prioritized. When irradiation cannot be avoided, BT allows minimizing patient body radiation dose. Patients < 10 years of age more frequently show embryonal RMS, while those ≥ 10 years old more frequently have alveolar RMS. In addition to this correlation, age was found to be an independent prognostic factor in RMS. Thus, patients aged ≥10 years have a poorer prognosis after adjusting on other risk factors, such as tumour stage, histology, and nodal status. It has also been shown that failure-free survival was lower for infants (≤ 1 year), due to a higher risk of local failure. This may be in relation to the fact that complete local treatment including radiotherapy is highly challenging to deliver in these patients and in this context BT has potentially a major role to achieve local control and avoid the long-term side effects of external irradiation.