Persistence of radiation-induced aberrations in patients after radiotherapy with C-ions and IMRT.

BACKGROUND AND PURPOSE: Chromosomal aberrations in peripheral blood lymphocytes are a biomarker for radiation exposure and are associated with an increased risk for malignancies. To determine the long-term cytogenetic effect of radiotherapy, we analyzed the persistence of different aberration types up to 2.5 years after the treatment. MATERIALS AND METHODS: Cytogenetic damage was analyzed in lymphocytes from 14 patients that had undergone C-ion boost + IMRT treatment for prostate cancer. Samples were taken immediately, 1 year and 2.5 years after therapy. Aberrations were scored using the multiplex fluorescence in situ hybridization technique and grouped according to their transmissibility to daughter cells. RESULTS: Dicentric chromosomes (non-transmissible) and translocations (transmissible) were induced with equal frequencies. In the follow-up period, the translocation yield remained unchanged while the yield of dicentrics decreased to ≈40% of the initial value (p = 0.011 and p = 0.001 for 1 and 2.5 years after compared to end of therapy). In 2 patients clonal aberrations were observed; however they were also found in samples taken before therapy and thus were not radiotherapy induced. CONCLUSION: The shift in the aberrations spectrum towards a higher fraction of translocations indicates the exposure of hematopoietic stem and progenitor cells underlining the importance of a careful sparing of bone marrow during radiotherapy to minimize the risk for secondary cancers.

High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years' experience with raster-scanned carbon ion therapy.

PURPOSE: Locoregional control (LC) in malignant salivary gland tumors is dose-dependent, initial results with particle therapy were promising. We report our experience with raster-scanned, intensity-controlled carbon ion therapy (C12) and IMRT in 309 patients with pathologically confirmed adenoid cystic carcinoma (ACC) of the head and neck. PATIENTS AND METHODS: Treatment records of patients treated with C12 between 08/1998 and 05/2013 were evaluated regarding tumor stage, treatment, toxicity (CTCAE v3), LC, progression-free survival (PFS) and overall survival (OS). Response assessment was carried out according to RECIST1.1. RESULTS: Tumor stages were mostly advanced (T4a/b: 60%, macroscopic disease: 71%), most common sites of origin were the paranasal sinus (37%). At a median follow-up at 33.9 months, LC, PFS, and OS at 3 and 5 year estimates are 83.7%/58.5%, 67.8%/56.1%, and 88.9%/74.6%. LC correlates with T-stage but neither nodal stage, age, relapse state, nor margin status. RECIST did not correlate with LC or survival rates. CONCLUSION: IMRT plus C12 boost results in good control and survival rates at moderate toxicity. Margin status did not correlate with LC in T4 tumors, extensive and potentially mutilating surgical procedures may have to be re-evaluated. RECIST assessment did not correlate with either LC or survival rates; potentially more meaningful radiological parameters need to be developed.

COSMIC: A Regimen of Intensity Modulated Radiation Therapy Plus Dose-Escalated, Raster-Scanned Carbon Ion Boost for Malignant Salivary Gland Tumors: Results of the Prospective Phase 2 Trial.

PURPOSE: To investigate the effect of intensity modulated radiation therapy (IMRT) and dose-escalated carbon ion (C12) therapy in adenoid cystic carcinoma (ACC) and other malignant salivary gland tumors (MSGTs) of the head and neck. PATIENTS AND METHODS: COSMIC (combined treatment of malignant salivary gland tumors with intensity modulated radiation therapy and carbon ions) is a prospective phase 2 trial of 24 Gy(RBE) C12 followed by 50 Gy IMRT in patients with pathologically confirmed MSGT. The primary endpoint is mucositis Common Terminology Criteria grade 3; the secondary endpoints are locoregional control (LC), progression-free survival (PFS), overall survival (OS), and toxicity. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3; treatment response was scored according to Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: Between July 2010 and August 2011, 54 patients were accrued, and 53 were available for evaluation. The median follow-up time was 42 months; patients with microscopically incomplete resections (R1, n = 20), gross residual disease (R2, n = 17), and inoperable disease (n = 16) were included. Eighty-nine percent of patients had ACC, and 57% had T4 tumors. The most common primary sites were paranasal sinus (34%), submandibular gland, and palate. At the completion of radiation therapy, 26% of patients experienced grade 3 mucositis, and 20 patients reported adverse events of the ear (38%). The most common observed late effects were grade 1 xerostomia (49%), hearing impairment (25%, 2% ipsilateral hearing loss), and adverse events of the eye (20%), but no visual impairment or loss of vision. Grade 1 central nervous system necrosis occurred in 6%, and 1 grade 4 ICA hemorrhage without neurologic sequelae. The best response was 54% (complete response/partial remission). At 3 years, the LC, PFS, and OS were 81.9%, 57.9%, and 78.4%, respectively. No difference was found regarding resection status. The most common site of failure was distant (55%). Local relapse was predominantly in field (79%). CONCLUSION: Treatment was tolerated, with moderate acute and late toxicity. The LC at 3 years was promising. No significant difference could be shown regarding resection status; hence, extensive and mutilating surgical procedures should be rediscussed. Further dose escalation may be limited in view of potential vascular adverse events.

Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival.

BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.

Re-irradiation of adenoid cystic carcinoma: analysis and evaluation of outcome in 52 consecutive patients treated with raster-scanned carbon ion therapy.

BACKGROUND: Treatment of local relapse in adenoid cystic carcinoma (ACC) following prior radiation remains a challenge: without the possibility of surgical salvage patients face the choice between palliative chemotherapy and re-irradiation. Chemotherapy yields response rates around 30% and application of tumouricidal doses is difficult due to proximity of critical structures. Carbon ion therapy (C12) is a promising method to minimize side-effects and maximize re-treatment dose in this indication. We describe our initial results for re-irradiation in heavily pre-treated ACC patients. METHODS: Patients treated with carbon ion therapy between 04/2010 and 05/2013 (N=52pts, median age: 54 a) were retrospectively evaluated regarding toxicity (NCI CTC v.4), tumour response (RECIST) and control rates. 48pts (92.3%) received carbon ions only, 4pts received IMRT plus C12. RESULTS: 4pts were treated following R1-resection, 43pts for inoperable local relapse. Most common tumour sites were paranasal sinus (36.5%), parotid (19.2%), and base of skull (17.3%). Pts received a median dose of 51GyE C12/63Gy BED and cumulative dose of 128Gy BED [67-182Gy] after a median RT-interval of 61months. Median target volume was 93ml [9-618ml]. No higher-grade (>°II) acute reactions were observed, 7pts showed blood-brain-barrier changes (°I/II: 8pts; °III: 2pts), 1 pt corneal ulceration, xerophthalmia 7pts, °IV bleeding 1 pt, tissue necrosis 2pts, otherwise no significant late reactions. Objective response rate (CR/PR) was 56.6%. With a median follow-up of 14months [1-39months] local control and distant control at 1a are 70.3% and 72.6% respectively. Of the 18pts with local relapse, 13pts have recurred in-field, 1 pt at the field edge, 3pts out of field, and one in the dose gradient. CONCLUSION: Despite high applied doses, C12 re-irradiation shows moderate side-effects, response rates even in these heavily pre-treated patients are encouraging and present a good alternative to palliative chemotherapy. Though most local recurrences occur within the high-dose area, further dose escalation should be viewed with caution.

Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis.

BACKGROUND: To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123). METHODS: Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31). RESULTS: Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years. CONCLUSION: Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up. TRIAL REGISTRATION: NCT01566123.

A clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma.

BACKGROUND: Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered. METHODS/DESIGN: The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50-56 Gy) followed by surgery and IORT (10-12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population. DISCUSSION: The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity. TRIAL REGISTRATION: NCT01566123.

IMRT and carbon ion boost for malignant salivary gland tumors: interim analysis of the COSMIC trial.

BACKGROUND: The COSMIC trial is designed to evaluate toxicity in dose-escalated treatment with intensity-modulated radiotherapy (IMRT) and carbon ion boost for malignant salivary gland tumors (MSGT) of the head and neck including patients with inoperable/ incompletely resected MSGTs (R2-group) and completely resected tumors plus involved margins or perineural spread (R1-group). METHODS: COSMIC is a prospective phase II trial of IMRT (25 × 2 Gy) and carbon ion boost (8 × 3 GyE). Primary endpoint is mucositis CTC°III, secondary endpoints are local control, progression-free survival, and toxicity. Evaluation of disease response is carried out according to the Response Evaluation Criteria in Solid Tumors (RECIST); toxicity is assessed using NCI CTC v 3.0. RESULTS: Twenty-nine patients were recruited from 07/2010 to 04/2011, all patients have at least completed first follow-up. Sixteen patients were treated in the R2-group, 13 in the R1-group. All treatments were completed as planned and well tolerated, mucositis CTC grade III was 25% (R2) and 15.4% (R1), no dysphagia CTC grade III was observed, no feeding tubes were necessary. Side-effects rapidly resolved, only 4 patients (13.8%) reported xerostomia grade II at first follow-up. Overall response rate (complete and partial response) according to RECIST in the R2-group is 68.8% at 6-8 weeks post treatment, all patients within this group showed radiological signs of treatment response. CONCLUSION: No unexpected toxicity was observed, mucositis rates and other side effects do not differ between patients with visible residual tumor and macroscopically completely resected tumors. Initial treatment response is promising though longer follow-up is needed to assess local control. TRIAL REGISTRATION: Clinical trial identifier NCT 01154270.

Radiochemoimmunotherapy with intensity-modulated concomitant boost: interim analysis of the REACH trial.

PURPOSE: To evaluate efficacy and toxicity clinical in the intensified treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) with the combination of chemotherapy, the EGFR antibody cetuximab, and intensity-modulated radiation therapy (IMRT) in a concomitant boost concept. METHODS: REACH is a prospective, bi-centric phase II trial of carboplatin/5-FU and cetuximab weekly combined with IMRT. Primary endpoint is locoregional control, secondary endpoints include acute radiation effects and adverse events. Evaluation of disease response is carried out according to the Response Evaluation Criteria in Solid Tumors (RECIST); toxicity is assessed using NCI CTC v 3.0. RESULTS: Treatment was tolerated moderately well, acneiforme erythema occurred in 74.1% (grade II/III), mucositis grade III in 28.6%, and radiation dermatitis grade III in 14.3%. Higher-grade side-effects resolved quickly until the first follow-up post treatment. Objective response rates were promising with 28.6% CR at first follow-up and 92.9% thereafter. CONCLUSION: The combination of standard carboplatin/5-FU and cetuximab is feasible and results in promising objective response rates. The use of an IMRT concomitant boost is practicable in a routine clinical setting resulting in only moderate overall toxicity of the regimen. TRIAL REGISTRATION NUMBER: ISRCTN87356938.

Raster-scanned carbon ion therapy for malignant salivary gland tumors: acute toxicity and initial treatment response.

BACKGROUND AND PURPOSE: To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+). METHODS: From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable. RESULTS: 103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up.47 patients showed good treatment responses (CR/PR) according to RECIST. CONCLUSION: Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control.

Acute toxicity of combined photon IMRT and carbon ion boost for intermediate-risk prostate cancer - acute toxicity of 12C for PC.

BACKGROUND: Carbon ion ((12)C) therapy in the treatment of prostate cancer (PC) might result in an improved outcome as compared to low linear energy transfer irradiation techniques. In this study, we present the first interim report of acute side effects of the first intermediate-risk PC patients treated at the GSI (Gesellschaft für Schwerionenforschung) and the University of Heidelberg in an ongoing clinical phase I/II trial using combined photon intensity modulated radiation therapy (IMRT) and (12)C carbon ion boost. MATERIAL AND METHODS: Fourteen patients (planned accrual: 31 pts) have been treated within this trial so far. IMRT is prescribed to the median PTV at a dose of 30 × 2 Gy; (12)C boost is applied to the prostate (GTV) at a dose of 6 × 3 GyE using raster scan technique. Safety margins added to the clinical target volume were determined individually for each patient based on five independent planning computed tomography (CT)-scans. Acute gastrointestinal (GI) and genitourinary (GU) toxicity was assessed and documented according to the CTCAE Version 3.0. RESULTS: Radiotherapy was very well tolerated without any grade 3 or higher toxicity. Acute anal bleeding grade 2 was observed in 2/14 patients. Rectal tenesmus grade 1 was reported by three other patients. No further GI symptoms have been observed. Most common acute symptoms during radiotherapy were nocturia and dysuria CTC grade 1 and 2 (12/14). There was no severe acute GU toxicity. CONCLUSION: The combination of photon IMRT and carbon ion boost is feasible in patients with intermediate-risk PC. So far, the treatment has been well tolerated. Acute toxicity rates were in good accordance with data reported for high dose IMRT alone.

Treatment of malignant sinonasal tumours with intensity-modulated radiotherapy (IMRT) and carbon ion boost (C12).

BACKGROUND: Most patients with cancers of the nasal cavity or paranasal sinuses are candidates of radiation therapy either due incomplete resection or technical inoperability. Local control in this disease is dose dependent but technically challenging due to close proximity of critical organs and accompanying toxicity. Modern techniques such as IMRT improve toxicity rates while local control remains unchanged. Raster-scanned carbon ion therapy with highly conformal dose distributions may allow higher doses at comparable or reduced side-effects. METHODS/DESIGN: The IMRT-HIT-SNT trial is a prospective, mono-centric, phase II trial evaluating toxicity (primary endpoint: mucositis ≥ CTCAE°III) and efficacy (secondary endpoint: local control, disease-free and overall survival) in the combined treatment with IMRT and carbon ion boost in 30 patients with histologically proven (≥R1-resected or inoperable) adeno-/or squamous cell carcinoma of the nasal cavity or paransal sinuses. Patients receive 24 GyE carbon ions (8 fractions) and IMRT (50 Gy at 2.0 Gy/fraction). DISCUSSION: The primary objective of IMRT-HIT-SNT is to evaluate toxicity and feasibility of the proposed treatment in sinonasal malignancies. TRIAL REGISTRATION: Clinical trial identifier NCT 01220752.

Carbon ion therapy for advanced sinonasal malignancies: feasibility and acute toxicity.

PURPOSE: To evaluate feasibility and toxicity of carbon ion therapy for treatment of sinonasal malignancies. First site of treatment failure in malignant tumours of the paranasal sinuses and nasal cavity is mostly in-field, local control hence calls for dose escalation which has so far been hampered by accompanying acute and late toxicity. Raster-scanned carbon ion therapy offers the advantage of sharp dose gradients promising increased dose application without increase of side-effects. METHODS: Twenty-nine patients with various sinonasal malignancies were treated from 11/2009 to 08/2010. Accompanying toxicity was evaluated according to CTCAE v.4.0. Tumor response was assessed according to RECIST. RESULTS: Seventeen patients received treatment as definitive RT, 9 for local relapse, 2 for re-irradiation. All patients had T4 tumours (median CTV1 129.5 cc, CTV2 395.8 cc), mostly originating from the maxillary sinus. Median dose was 73 GyE mostly in mixed beam technique as IMRT plus carbon ion boost. Median follow-up was 5.1 months [range: 2.4-10.1 months]. There were 7 cases with grade 3 toxicity (mucositis, dysphagia) but no other higher grade acute reactions; 6 patients developed grade 2 conjunctivits, no case of early visual impairment. Apart from alterations of taste, all symptoms had resolved at 8 weeks post RT. Overall radiological response rate was 50% (CR and PR). CONCLUSION: Carbon ion therapy is feasible; despite high doses, acute reactions were not increased and generally resolved within 8 weeks post radiotherapy. Treatment response is encouraging though follow-up is too short to estimate control rates or evaluate potential late effects. Controlled trials are warranted.

Randomised trial of proton vs. carbon ion radiation therapy in patients with chordoma of the skull base, clinical phase III study HIT-1-Study.

BACKGROUND: Chordomas of the skull base are relative rare lesions of the bones. 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. Level of recurrence after surgery alone is comparatively high, so adjuvant radiation therapy is very important for the improvement of local control rates. Proton therapy is the gold standard in the treatment of skull base chordomas. However, high-LET beams such as carbon ions theoretically offer biologic advantages by enhanced biologic effectiveness in slow-growing tumors. METHODS/DESIGN: This clinical study is a prospective randomised phase III trial. The trial will be carried out at Heidelberger Ionenstrahl-Therapie centre (HIT) and is a monocentric study.Patients with skull base chordoma will be randomised to either proton or carbon ion radiation therapy. As a standard, patients will undergo non-invasive, rigid immobilization and target volume delineation will be carried out based on CT and MRI data. The biologically isoeffective target dose to the PTV in carbon ion treatment (accelerated dose) will be 63 Gy E ± 5% and 72 Gy E ± 5% (standard dose) in proton therapy respectively. Local-progression free survival (LPFS) will be analysed as primary end point. Toxicity and overall survival are the secondary end points. Additional examined parameters are patterns of recurrence, prognostic factors and plan quality analysis. DISCUSSION: Up until now it was impossible to compare two different particle therapies, i.e. protons and carbon ions directly at the same facility.The aim of this study is to find out, whether the biological advantages of carbon ion therapy can also be clinically confirmed and translated into the better local control rates in the treatment of skull base chordomas. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01182779.

Randomised trial of proton vs. carbon ion radiation therapy in patients with low and intermediate grade chondrosarcoma of the skull base, clinical phase III study.

BACKGROUND: Low and intermediate grade chondrosarcomas are relative rare bone tumours. About 5-12% of all chondrosarcomas are localized in base of skull region. Low grade chondrosarcoma has a low incidence of distant metastasis but is potentially lethal disease. Therefore, local therapy is of crucial importance in the treatment of skull base chondrosarcomas. Surgical resection is the primary treatment standard. Unfortunately the late diagnosis and diagnosis at the extensive stage are common due to the slow and asymptomatic growth of the lesions. Consequently, complete resection is hindered due to close proximity to critical and hence dose limiting organs such as optic nerves, chiasm and brainstem. Adjuvant or additional radiation therapy is very important for the improvement of local control rates in the primary treatment. Proton therapy is the gold standard in the treatment of skull base chondrosarcomas. However, high-LET (linear energy transfer) beams such as carbon ions theoretically offer advantages by enhanced biologic effectiveness in slow-growing tumours. METHODS/DESIGN: The study is a prospective randomised active-controlled clinical phase III trial. The trial will be carried out at Heidelberger Ionenstrahl-Therapie (HIT) centre as monocentric trial. Patients with skull base chondrosarcomas will be randomised to either proton or carbon ion radiation therapy. As a standard, patients will undergo non-invasive, rigid immobilization and target volume definition will be carried out based on CT and MRI data. The biologically isoeffective target dose to the PTV (planning target volume) in carbon ion treatment will be 60 Gy E ± 5% and 70 Gy E ± 5% (standard dose) in proton therapy respectively. The 5 year local-progression free survival (LPFS) rate will be analysed as primary end point. Overall survival, progression free and metastasis free survival, patterns of recurrence, local control rate and morbidity are the secondary end points. DISCUSSION: Up to now it was impossible to compare two different particle therapies, i.e. protons and carbon ions, directly at the same facility in connection with the treatment of low grade skull base chondrosarcomas.This trial is a phase III study to demonstrate that carbon ion radiotherapy (experimental treatment) is not relevantly inferior and at least as good as proton radiotherapy (standard treatment) with respect to 5 year LPFS in the treatment of chondrosarcomas. Additionally, we expect less toxicity in the carbon ion treatment arm. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01182753.