Nikoghosyan et al. BMC Cancer 2010, 10:607 http://www.biomedcentral.com/1471-2407/10/607 Inclusion criteria - Karnofsky Performance Score ≥60% - Age >18 years and <80 years - Informed consent signed by the patient - Histological confirmation of chordoma with infiltra- tion of the skull base. Exclusion criteria - Inability to understand the aims of the study, no informed consent - Prior RT of skull base region - Other malignancies with disease-free interval < 5 years (excepting pre-cancerous lesions) - Participation in another trial - Pregnancy - Simultaneous CHT or Immunotherapy. Risk group definition Secondary objectives of the study will be explorative analysed also according to risk groups mentioned in Table 1. Randomisation The randomisation will be done using the on-line ran- domisation tool (Randomizer.at) which is self-serve and runs exclusively on the Internet. An on-screen form with patient details will be completed. The treatment allocation will be immediately notified. The randomisa- tion will be performed regarding treatment arms A and B. Stratification parameters include the following cri- teria: age (< 30, ≥ 30 years) and gender. As this is an open-label study there will be no blinding of treatment assignment. Reference Committee In order to monitor specific aspects of the current trial the Data Monitoring Committee (DMC) will be estab- lished. The work of Date Monitoring Committee will be based on the Guideline on Data Monitoring Committees EMEA/CHMP/EWP/5872/03. The DMC will be com- posed of independent experts in the field of radiation oncology, assessing the progress of the trial and avail- able safety data. The mission of the DMC will be to ensure the ethical conduct of the trial and to protect the safety interests of patients in this trial. Table 1 Risk group characterization Low-risk Age > 30 years Male chordoma No OAR compression Primary tumour Tumour size < 70 ml High-risk Age ≤ 30 years Female chordoma Compression of OAR Recurrent tumor Tumour size > 70 ml Page 4 of 9 Radiation therapy Immobilisation Patients will be immobilized using a precision head mask to ensure high repositioning accuracy of the target volume and adjacent structures for carbon ion and pro- ton RT. Safety margins around the clinical target volume (CTV) will be determined individually for each patient. Positioning accuracy will be controlled using orthogonal x-rays or cone-beam-CTs. Set-up deviations will be corrected prior to irradiation by correction with the vector of the robotic table. Treatment planning examinations/Target definition The treatment planning CT (obligate native CT, CT with contrast facultative) and MR - Examination (MRT - compulsory sequences - axial T1 post gadolinium and T2 fat saturated or Flair) will be performed in treatment position using the immobilisation device and will be co- registered. The treatment planning CT will consist of continuous 3 mm slices obtained in a stereotactic or vir- tual simulation set-up. The delineation of organs at risk and target volume definition will be done on the basis of CTs and MRI scans. The PTV1 should include the GTV (entire resi- dual tumour) and a 1-2 mm safety margin. PTV2 includes the PTV1 with individual safety margin based on surgical and histological reports, and MR-images to account for subclinical disease. The PTV2 includes the whole clivus and the prevertebral muscles down to the basis of the second cervical vertebra in any case. Normal tissue constrains will be defined as follows: eyes, optic nerves, chiasm, brainstem, spinal cord obligatory, tem- poral lobes, mandible, salivary glands and others faculta- tively. An overlap of the PTV and the OAR needs to be avoided. Carbon ion/Proton RT Carbon ion RT planning is performed using the treat- ment planning software including biological plan opti- mization for carbon ions. Two to maximum four irradiation fields will be chosen. At HIT the intensity- controlled raster-scan system will be used for beam application. Considering the tolerance dose to organs at risk a dose of 63 Gy E ± 5% in 20-22 fractions for car- bon ions and 72 Gy E ± 5% in 34-37 fractions for pro- tons for chordoma patients will be prescribed to the maximum of the calculated dose distribution for the tar- get volume (PTV1). Treatment planning aims at cover- age of the PTV1 and PTV2 with the 95%-isodose line of the prescribed dose. For carbon ion therapy dose specification is based on biologic equivalent dose because of the higher relative biologic effectiveness (RBE) of carbon ions, which differs