The decision for or against radiotherapy is therefore a question of priorities of the treating physician and of the patient/parents

Appendix eI: Radiotherapy guidelines for orbital rhabdomyosarcoma as defined in the EpSSG RMS 2005 protocol¹⁰

The decision for or against radiotherapy in patients with group II and group III embryonal rhabdomyosarcoma and clinical complete remission following induction chemotherapy is made individually following full informed consent. Patients in this treatment situation who receive radiotherapy have a lower risk of local relapse, an improved event free survival but experience radiation associated side effects. Patients in this treatment situation who do not receive radiotherapy have a higher risk of local relapse, less good event free survival but no radiation associated side effects in case there is no local relapse and increased toxicity due to salvage treatment including radiotherapy if a relapse occurs. Overall survival in both approaches is equivalent. This is due to effective salvage treatment. The decision for or against radiotherapy is therefore a question of priorities of the treating physician and of the patient/parents. Two options are given in this protocol.

When given, radiation of the entire orbit is performed up to 36 Gy, then the PTV (planning target volume) is reduced to the initial tumor size and an additional margin of 1 cm, if possible sparing the lacrimal gland. Patients with favorable histology and clinical complete remission following induction chemotherapy receive 41.1 Gy, patients with partial response (see “Response classification as defined in the EpSSG RMS 2005 protocol”, specified below) 45 Gy, patients with minor partial response, stable disease or progressive disease receive 50.4 Gy.

Appendix eII: Risk factors evaluated

1. Classical prognostic risk factors for rhabdomyosarcoma: age at diagnosis, histology, primary tumor site, size, extent, erosion of bony boundaries (including cranial base bony erosion (CBBE)), bone involvement, chemotherapy regimen (agents and number of courses), response to induction chemotherapy

2. Tumor site and extension: the orbit was divided into the following areas: superior, supero- nasal, supero-temporal, temporal, infero-temporal, inferior, infero-nasal and nasal. Relation of the tumor with the following orbital structures was evaluated: lacrimal gland, nasolacrimal duct, lacrimal sac, extra-ocular muscles), involvement of the apex, bony erosion and bone invasion; these are all factors that may affect resectability and eye function. If the tumor invaded parameningeal sites (Appendix eIII), localization was considered parameningeal.

3. Surgical risk factors: type of initial surgery (fine needle aspiration (FNAC), incisional biopsy, excisional biopsy), surgical risk factors, completeness of tumor resection, histopathologic analysis of the resected specimen (microscopic remnants, vital tumor cells),

4. Radiotherapy risk factors: adequacy of isodose distribution of brachytherapy/EBRT (external beam radiotherapy), dose and dose rate or fractionation. In patients with local recurrent disease, the site of recurrence was described as being within the residual (post-

chemotherapy) area or initial (pre-chemotherapy) tumor area.

Appendix eIII: Response classification as defined in the EpSSG RMS 2005 protocol¹⁰ Complete remission (CR) Complete disappearance of all visible disease Partial response (PR) Tumor volume reduction ≥66% but <99%

Minor partial response (mPR) Tumor volume reduction >33% but <66%

Stable disease (SD) No criteria for PR or PD (<33% tumor volume reduction) Progressive disease (PD) Any increase of more than 40% in volume (or >25% in area)

of any measurable lesion, or appearance of new lesions.

Appendix eIV: Parameningeal extension as defined in the EpSSG RMS 2005 protocol¹⁰ 1. Middle ear

This refers to a primary that begins medial to the tympanic membrane. This tumor is often advanced at presentation and because of extension laterally may present with a mass in front of or under the ear suggesting parotid origin. It may also extend through the tympanic membrane and appear to be arising in the ear canal. When there is doubt about the site of origin, the “middle ear” designation should be picked as it implies more aggressive therapy required of parameningeal sites.

2. Nasal cavity and Para nasal Sinuses

The three Para nasal sinuses are the maxillary sinuses, the ethmoid sinuses, and the sphenoid sinus. These surround the nasal cavity, and a primary in one will frequently extend to

another. It can be difficult to determine the exact site of origin, but the choice is academic as the treatment is not affected. The site designation will have a bearing on the design of radiotherapy portals. Tumor arising in the maxillary or ethmoid sinuses may invade the orbit.

This is much more likely than a primary in the orbit invading one of the sinuses. When the distinction betwee orbit and Para nasal sinus is unclear, the selected should be Para nasal sinus as it is the more likely primary site and requires appropriately more aggressive therapy.

A primary arising in the sphenoid sinus (rare) may extend inferiorly to involve the nasopharynx.

3. Nasopharynx

This refers to the superior portion of the pharynx which is bounded anteriorly by the back of the nasal septum, superiorly by the sphenoid sinus, inferiorly by a level corresponding to the soft palate, and laterally and posteriorly by the pharyngeal walls.

4. Infatemporal Fossa/Pterygopalatin and Parapharyngeal Area

This refers to the tissues bounded laterally by the medial lobe of the parotid gland and medially by the pharynx. Large tumors in this region may extend through the parotid gland and present as a mass of the lateral face, sometimes extending even to the cheek. Where there is doubt as to the primary, the parameningeal designation should be chosen as it confers appropriately more aggressive treatment. The superior boundary of this tissue volume is the base of skul just under the temporal lobe, hence the term “infratemporal’. The distinction between this and the “parapharyngeal” area is academic.

5. Orbital tumors with bone erosion

Tumors arising in the orbit but with intracranial extension or important bone erosion are included in the parameningeal group.

In addition the following are classified as parameningeal tumors:

 Tumors involving vessels or nerves with with direct intracranial connection (arteria carotis interna, vertebralis, N. opticus, trigeminus, facialis etc).

 All intracranial and intraspinal tumors (but tumors arising from the paraspinal muscles with intraspinal extension should be designated as paraspinal, see “Other site” definition).

 All tumors with cranial nerve paresis (excluding parotid tumors with facial nerve palsy).

 CSF Tumor cell positive patients.