Nikoghosyan et al. BMC Cancer 2010, 10:607 http://www.biomedcentral.com/1471-2407/10/607 Table 3 Workflow time table Page 6 of 9 Approval of ethics committee ↓ Diagnosis of chordoma of the skull base and completion of pre-radiation treatment examinations (biopsy, operation, staging) ↓ Informed consent of the patient and patient registration by the study office at HIT ↓ Stratification and Randomisation ↓ Arm A: carbon ion RT (63 Gy E ± 5%, fractionation 4-6 × 3.0 Gy E) Arm B: proton RT (72 Gy E ± 5%, fractionation 4-6 × 2.0 Gy E) ↓ Treatment planning for particle therapy ↓ Particle therapy ↓ Follow-up Scoring Scheme will be used to grade toxicity from radiation therapy occurring later than 90 days after its start, i.e. beyond the 1st follow-up visit. All late radia- tion effects will be documented on a Late Radiation Effect-Form. In addition, an AE-Form and/or SAE-Form will be filled out, if late radiation effects appear. The follow-up examinations contain: - Medical history - Clinical examination - MRI or CT of the head - Documentation of acute side effects/AE (CTCAE V.4.0) up to 90 days after RT - Documentation of late side effects/AE (RTOG/ EORTC) after 90 days after RT - Reporting/documentation of acute grade 3 or 4 toxi- city or grade 3, 4 or 5 late effects. Study duration and interruption criteria Accrual period for the trial will be approximately 5 years starting on autumn 2010. The study ends with the enrollment of planned 344 patients. Our study design contains interim analysis after observation period of 7 years. Definite assessments of LPFS, survival and for radiation specific AEs will be possible approximately 8 years after completion of radiation therapy of the last recruited patient. The individual reasons for the study interruption are the patient dead or the withdrawing agreement of the patient to participate in the study. With proven recurrence of disease or the development of distant metastases, the patient will be censored for our study and will be eligible for any additional appro- priate therapy or inclusion in other investigative proto- cols, but should still be followed in order to document survival and radiation specific AEs. The study can be early terminated under following considerations: - high incidence of unknown AEs or increase in known AEs with the disadvantageous proportion between risk and benefits of the proposed radiation therapy; - unacceptable high rates of SAEs; - other reasons challenging the ethical basis; - official decision. All subjects who have adverse events, whether consid- ered associated with the therapy, must be monitored to determine the outcome. The clinical course of the adverse event will be followed up according to accepted standards of medical practice, even after the end of the period of observation, until a satisfactory explanation is found or the investigator considers it medically justifiable to terminate follow-up. Should the adverse event result in death, a full pathologist’s report should be supplied, if possible. Each adverse event occurring in connection with the therapy has to be documented, independent of the cause. Statistical Considerations and Analysis Study Hypothesis This study is designed to demonstrate that carbon ion therapy can significantly improve LPFS compared with proton therapy in the treatment of skull base chordo- mas. Primary objective is the comparison of the two treatment groups. Null hypothesis H0: The survival functions of LPFS of the two therapies are equal, hazard ratio = 1. Alternative hypothesis H1: The survival functions of LPFS of the two therapies are not equal, hazard ratio ≠ 1.