The study plan has been submitted to the ethics committee of the Medical faculty Heidelberg and is already approved. Also the positive vote of Bundesamt für Strahlenschutz (the governmental authority for radiation protection in Germany) has been already obtained.
The study is a double arm prospective randomised clinical phase III study of patients with low/intermediate grade chondrosarcomas of the skull base. Study patients are selected according to the inclusion criteria of the study protocol. After careful review of the patient reports and results of the additional examinations eligibility of a patient will be determined.
The randomisation will be done using the on-line randomisation tool (Randomizer.at) which is self-serve and runs exclusively on the Internet. The randomisation will be performed regarding treatment arms A and B. Patients will be randomized to the treatment groups with an equal allocation ratio of 1:1.
As this is an open-label study there will be no blinding of treatment assignment.
Primary objectives of the study
The primary objective of this study is to evaluate, if the innovative therapy (carbon ion irradiation) in chondrosarcomas is not relevantly inferior to the standard proton treatment with respect to the 5 year LPFS rate defined as time from the randomisation to observed local recurrence. Withdrawals, lost to follow-ups and patients for whom no event has occurred at study termination are treated as censored observations. The censoring date is given by the last known date at which no event has occurred for the respective patient. Local recurrence defined as MRT or CT - morphological tumour progress in the former irradiated region. It is assumed that the LPFS rate for the proton therapy is 90%.
Secondary objectives of the study
Assessment of overall survival, progression free and metastasis free survival, patterns of recurrence, local control rate and morbidity (acute and late toxicity (Common Terminology Criteria for Adverse Events: CTCAE V4.0, RTOG/EORTC for late effects)) are the second objectives of the study. Plan quality (target coverage, sparing of organs at risk, integral dose) is also a matter of interest.
Karnofsky Performance Score ≥60%
Age >18 years and <80 years
Informed consent signed by the patient
Histological confirmation of low/intermediate grade chondrosarcoma with infiltration of the skull base.
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
Simultaneous CHT or Immunotherapy.
Pre-treatment examination such as history and physical examination including neurological status, histological confirmation of chondrosarcoma, reference-histopathology if necessary, ophthalmologic examination by optic nerve, chiasm infiltration or by contiguity, audiometry by auditory channel infiltration or by contiguity, endocrinological examination by contiguity to sella turcica region and MR - Imaging (before) and after operation will be done or/and collected.
Patients with histologically confirmed low and intermediate grade chondrosarcoma and infiltration of the skull base which are willing to participate will be included into our study after verification of the eligibility centrally at the HIT trial center. These patients are subsequently randomized to one of the two treatment arms (arm A: carbon ion therapy, arm B: proton therapy).
Carbon ion therapy (Arm A) will be aplicated with a total target dose of 60 Gy E ± 5% to the PTV1. The PTV2 will receive a total carbon ion dose of 45 Gy E.
The patients entered in Arm B will receive proton therapy with the same target definition concept. The total proton dose will be 70 Gy E ± 5%. The PTV2 will receive a total dose of 50 to 56 Gy E in conventional fractionation.
Accrual period for the trial will be approximately 7 years. Our study design contains one interim analysis after observation period of approximately 5.5 years. The study will be terminated early in case of interim analysis showing 5% smaller rate of the 5 year LPFS of the experimental treatment (carbon ion therapy) in respect to the 5 year LPFS rate of standard treatment (proton therapy). If it is not a case the study ends with the enrollement of planned 154 patients. Definite assessments of 5 year LPFS, primary and secondary endpoints will be performed 12 years after completion of radiation therapy.
In order to monitor specific aspects of the current trial the following Reference Data Monitoring Committee (DMC) will be established. The DMC will be composed of independent experts in the field of radiation oncology, assessing the progress of the trial and available 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.
The DMC will meet on a regular basis, i.e. once a year. Based on its review of available safety data (CRFs) the DMC will provide the sponsor with written recommendations regarding trial modification, continuation or termination.