Nikoghosyan et al. BMC Cancer 2010, 10:607 http://www.biomedcentral.com/1471-2407/10/607 Safety Analysis The safety analysis will be based on the safety popula- tion. The assessment of safety will be based mainly on the frequency of adverse events or serious adverse events the acute and late toxicities and on the number of laboratory values that fall outside of pre-determined ranges and/or show prominent worsening. Furthermore, the most common AEs (those occurring in at least 10% of the treatment group) will be determined. Any other information collected (e.g. severity or relatedness to study drug) will be listed as appropriate. Incidence rates and exact Pearson-Clopper 95% confidence bounds [27] of AE will be summarized. Interim Analysis There is one planned interim analysis. The purpose for performing the interim analysis is to support a possible early detection of the superior therapy. In case of reach- ing a critical value of 2.9626 in the interim analysis the underlying therapy should neither be used for any further patients treated within the study nor for any patients outside of the study. The interim analysis will be performed as soon as 50% of the expected events have occurred. Assuming that rate of recruitment proceeds at the rate estimated for this study the time of the interim analysis will be approxi- mately 7 years after the first patient is entered. This time point is after the end of recruitment. For this reason the interim analysis does not have the goal to stop the study early and should not define a critical value of early stop- ping for futility. Independent of the result of the interim analysis the study should continue as planned with the recruited and already treated patients. Interim statistical hypothesis tests will be performed only for the primary efficacy endpoint, LPFS. The log- rank test identical to the primary analysis will be per- formed at the scheduled interim analysis and compared to group sequential boundary based on the current information time. The LPFS curve estimated by the method of Kaplan-Meier will be summarized for each treatment group. The hazard ratio will also be esti- mated. The interim safety report will review all aspects of the data collected for each subject. Other important additional factors that reflect the integrity of the proto- col will be addressed in the interim report. A group sequential design with an O’Brien and Flem- ing alpha spending function is used to control the type I error. The nominal one-sided significance level for the interim analysis determined by using the O’Brien-Flem- ing stopping rule is 0.0015. Ethical and legal aspects The study plan has been submitted to the ethics com- mittee of the Medical faculty Heidelberg for approval. Page 8 of 9 The written approval by the ethics committee has been already obtained. Additionally, we received the positive vote of Bundesamt für Strahlenschutz for this study. Prior to initiation of the treatment, patients will be informed about the goals of the trial in a conversation. Potential advantages and treatment related risks will be discussed with the patient. A written consent will be obtained and documented. The patient will be informed about the possibility to withdraw his agreement to parti- cipate in the study at any time without giving reasons. The responsible physician will inform the patient in his own language if possible and keep a record of this in the patient chart. The informed consent form will be signed. In case of cancellation the patient will be offered standard therapy. The coordinating investigator has to subscribe to an insurance policy covering, in its terms and provisions, its legal liability for injuries caused to participating per- sons and arising out of this research performed strictly in accordance with the scientific protocol as well as with applicable law and professional standards. Any impairment of health which might occur in con- sequence of trial participation must be notified to the insurance company. The subject is responsible for notifi- cation. The insured person will agree with all appropri- ate measures serving for clarification of the cause and the extent of damage as well as the reduction of damage. During the conduct of the trial, the subject must not undergo other clinical treatment except for cases of emergency. The subject is bound to inform the investi- gator immediately about any adverse events and addi- tional drugs taken. The terms and conditions of the insurance will be handed out to the subject on request. The insurance company has to be informed about all amendments that could affect subjects’ safety. Discussion This study is designed as a prospective monocentric randomised phase III trial. The trial will be carried out at HIT centre. Proton therapy is the gold standard in the treatment of skull base chordomas. However, high- LET beams such as carbon ions theoretically offer biolo- gic advantages by enhanced biologic effectiveness in slow-growing tumours. Up until now it was impossible to compare two different particle therapies, i.e. proton and carbon ion therapy directly with each other at the same institution. The aim of this study is to find out, whether the biological advantages of carbon ion therapy mentioned above can also be clinically confirmed. Acknowledgements The trial is funded by Deutsche Forschungsgemeinschaft (DFG) Klinische Forschergruppe “Schwerionentherapie in der Radioonkologie” KFO 214. The