Nikoghosyan et al. BMC Cancer 2010, 10:607 http://www.biomedcentral.com/1471-2407/10/607 may behave more aggressively [5]. Men are affected more frequently than women. Surgical resection is the primary treatment standard, though complete resection is nearly impossible due to close proximity to critical and hence also dose limiting organs for radiation therapy i.e. optic nerves, chiasm and brainstem. Level of recurrence after surgery alone is with reported rates between 50% and 100% [6] compara- tively high, so adjuvant radiation therapy is very impor- tant for the improvement of local control rates in the primary treatment even after complete resection. Tumour volume is an important prognostic factor, hence a tumour debulking is usually required before radiation therapy application [7]. Other prognostic rele- vant risk factors are the histological tumour type, resec- tion status, gender, and the age of the patient [8,9]. Radiation resistance is a common characteristic of chordomas [10,11], so high total doses are needed to achive acceptable local control rates after radiotherapy. Conformal precision and image guided radiation therapy techniques provide a safe technique for dose escalation [12]. The physical characteristics of carbon ions or pro- tons such as inverted dose profile allow steep dose gra- dients and therefore provide further benefit in this field by potentially reducing toxicity. So far, proton therapy is the gold standard in treat- ment of rare skull-base tumours like chordoma and low grade chondrosarcoma. The Loma Linda University Medical Center (LLUMC) [13] and the Massachusetts General Hospital (MGH) in Boston [14] have the largest experience in particle therapy for these entities. 3-year local control for chordomas after fractionated proton radiation therapy in 33 patients at LLUMC was 67% and the actuarial 5 year survival rate was 79% respectively [14]. The outcome of 519 cases of chordomas and chon- drosarcomas of the skull base including 290 chordomas treated with a combination of proton and photon ther- apy at MGH/HCL shows a significant difference in local control and survival rates between the patients with chordoma and chondrosarcoma. 5- and 10-year local progression free survival was 98% and 94% for chondro- sarcomas and 73% and 54% for chordomas [13,14]. Proton therapy results from PSI in Villingen, Switzer- land were published by Weber et al. and showed 3 year local control rates of 87.5% for chordomas. However, the treated tumour volumes with a median GTV of 16.4 ml were relatively small. 29 patients, among them 18 patients with chordoma were treated to a median target dose of 74 GyE. The 3-year actuarial PFS rate for the entire patient cohort was 90% [15]. Carbon ions though, have a higher biological effective- ness than either protons or photons, which might improve the results of these radio-resistant tumours [16]. Carbon ion therapy is available only at the National Page 2 of 9 Institute of Radiological Sciences (NIRS) in Japan and up to July 2008 has been available at the Gesellschaft für Schwerionenforschung (GSI) Darmstadt in Germany. The experience of our Japanese colleagues is limited to 40 patients with chordoma and chondrosarcoma of the skull base who could be treated effectively and without serious side effects [17]. NIRS beam delivery technique relies on passive scanning necessitating various modula- tors to adjust for treatment depth and tissue inhomo- geneities within the beam path. In comparison to the Japanese centres, the facility at GSI as well as the Heidelberger Ionenstrahl-Therapie centre (HIT) relies on active beam delivery using the raster-scan technique. In prior series, each treatment plan was biologically optimized at GSI as well as at HIT (Figure 1). About 300 patients with base of skull chor- domas and chondrosarcomas have been treated so far. Initially, these patients were treated within a clinical Phase I/II study. This study was able to demonstrate excellent clinical results and carbon ion therapy became approved as the best therapy available in Germany. The actuarial local control rates for the chordoma patients after 3 and 5 years were 80.6% and 70%, the 3 and 5 year overall survival rates were 91.8% and 88.5%, respec- tively [18]. Methods and Design Primary objectives/endpoints of the study The primary objective of this study is to evaluate, if the innovative therapy (carbon ion irradiation) in chordomas is superior to the standard proton treatment with respect to the Local-progression free survival (LPFS) defined as time from the randomisation to observed local recurrence or death from any cause in the absence of documented local disease progression. Local recur- rence defined as MRT or CT - morphological tumour progress in the former irradiated region. A 10% increase in the LPFS is considered clinically relevant assuming that the LPFS rate for the proton therapy is 70%. Secondary objectives of the study 1. Assessment of overall survival, progression free and metastasis free survival, patterns of recurrence, local control rate and morbidity. 2. Prognostic factors, definition of patients who will benefit from the adjuvant therapy, risk group definition. 3. Plan quality (target coverage, sparing of organs at risk, integral dose). Study design/concept The study is a double arm prospective randomised clini- cal phase III study of patients with chordomas of the