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

Low and intermediate grade chondrosarcomas (9-13% of all malignant bone tumours) are relative rare bone tumours. In 5-12% of all cases the chondrosarcomas are localized in head-and-neck region [1]. The typical sites of skull base lesions are temporo-occipital junction, parasellar area, spheno-ethmoid region and clivus [2, 3]. Due to hystopathological type chondrosarcomas are divided into Grade 1 to 3 tumours according to mitotic rates (WHO classification) with 3 histological subgroups: classic, mesenchymal and myxoid [2]. The mesenchymal type has more aggressive growth behaviour and is associated with a poorer prognosis. Histological differentiation from chordomas is often difficult and must contain immunhistochemical staining [2, 4]. Chordoma is immunopositive for epithelial markers like cytokeratin and endothelial membrane antigen (EMA), whereas chondrosarcoma is negative for both. Both chordomas and chondrosarcomas can be positive for S-100 and vimentin [5].

Most patients diagnosed are over the age of 40 years. Low grade chondrosarcoma has a low incidence of distant metastasis but is potentially lethal disease. Thus, local therapy has a 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 size of the tumours are common due to the slow growth kinetics; most patients are asymptomatic, or develop symptoms at a late stage of the disease. Consequently, complete resection is hindered due to close proximity to critical and hence dose limiting organs for radiation therapy i.e. optic nerves, chiasm and brainstem. Adjuvant or additional radiation therapy is very important for the improvement of local control rates in the primary treatment even after complete resection (no compartment resection possible). Anyhow, chondrosarcoma have a better outcome and prognosis compared to chordoma [6, 7].

Chondrosarcomas are commonly radioresistant [8], and high local doses are required for long-term local control. Image guidance in conformal precision radiation therapy provides a safe technique in the treatment of base of skull tumours [9]. The highest dose conformality is possible using particle therapy with heavy ions and protons due to inverted dose profile allowing steep dose gradients and therefore providing further benefit in reducing toxicity and irradiation safety.

It is brightly accepted, that proton therapy can be considered the gold standard for treatment of rare skull-base tumours like chordoma and low grade chondrosarcoma [10]. Loma Linda University Medical Center (LLUMC) [8] the Massachusetts General Hospital (MGH) in Boston [11] have the longest experience in proton therapy for these entities. 3-year local control for chondrosarcomas after fractionated proton radiation therapy in 25 patients at LLUMC was 94% and the actuarial 5 year survival rate was 100% respectively [11].

The outcome in 229 chondrosarcomas treated with a combination of proton and photon therapy at MGH/HCL shows 5-and 10-year local progression free survival rate of 98% and 94% for chondrosarcomas respectively. The results are significantly better than in chordomas treated at the same institution [8].

Proton therapy results from PSI in Villingen, Switzerland were published by Weber et al. and Ares et. al. The data showed 3- and 5-year local control rates of 100% and 94%, respectively. 64 patients, among them 22 patients with chondrosarcoma were treated to a median target dose of 68.4 GyE. The 3-year actuarial overall survival rate for the chondrosarcoma patients was 91% [12, 13].

Carbon ions though, have a higher biological effectiveness than either protons or photons, which is important in case of radioresistant tumours [14].

Carbon ion therapy is available at the National Institute of Radiological Sciences (NIRS) in Japan and at Heidelberger Ionenstrahl-Therapie (HIT) centre. The report of our Japanese colleagues experience is limited to 40 patients with chordoma and chondrosarcoma of the skull base. The patients could be treated effectively and without serious side effects [15]. NIRS beam delivery technique relies on passive scanning necessitating various modulators to adjust for treatment depth and tissue inhomogeneities within the beam path.

Our experience is based on the clinical work at the Gesellschaft für Schwerionenforschung (GSI) Darmstadt in Germany up to July 2008. In comparison to the Japanese centres, the facility at GSI as well as the HIT relies on active beam delivery using the raster-scan technique. About 300 patients with base of skull chordomas and chondrosarcomas have been treated so far. Initially, these patients were treated within a clinical Phase I/II study. After the study was able to demonstrate successful treatment, carbon ion therapy became approved as the best therapy available in Germany. The actuarial local control rates for the chondrosarcoma patients after 3 and 5 years was 96.2% and 89.8% respectively, the 5 year overall survival rates was 98.2% [16].

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.

Patients will be immobilized using a precision head mask to ensure high repositioning accuracy of the target volume and adjacent structures for carbon ion and proton RT. The treatment planning CT (obligate native CT, CT with contrast facultative) and MR-Examination (MRT - compulsory sequences - axial T1 post gadolinium and T2 fat saturated or Flair fat saturated) will be performed in treatment position using the immobilisation device and will be co-registered. The treatment planning CT will consist of continuous 3 mm slices obtained in a stereotactic or virtual simulation set-up.

The delineation of organs at risk and target volume definition will be done on the basis of CTs and MRI scans. The CTV1 should include the GTV (entire residual tumour) and a 1-2 mm safety margin. CTV2 includes the CTV1 with individual safety margin based on surgical and histological reports, and MR-images to account for subclinical disease. The PTV will created adding safety margins around the CTV individually for each patient. The following organs at risk will be defined: eyes, optic nerves, chiasm, brainstem, spinal cord obligatory, temporal lobes, mandible, salivary glands and others facultative. An overlap of the CTV and the OAR needs to be avoided.

Patient data will be collected and documented pseudonymously using electronic data processing (e.g. patient initials, date of birth and study number) at the study office at HIT.

The study data as for example all medical reports, RT documentation and CRF's will be collected at the study office at HIT.

Local recurrences will be confirmed radiologically and histologically whenever possible. At least two medical doctors (radiation oncologist and/or radiologist) will be required to judge of the recurrence or toxicity. Each adverse event occurring in connection with the therapy has to be documented, independent of the cause.

The first and the second follow-up examination will be performed 4-6 weeks and 3 months after completion of RT (follow-up 1 and 2). Follow-up examinations will then be scheduled after 6 months (follow-up 3), 9-12 months (follow-up 4), and then once a year for further 3 years (follow-up 5, 6 and 7). Additional visits will be scheduled as necessary. Acute toxicity is assessed at least weekly during RT and documented at the end of the RT series, 6 weeks after completion of RT and 3 months after RT. Late toxicity will be documented in regular intervals of 6 or 12 months during the observation period. All the patients will be observed for radiation specific acute and late AEs for the time of at least 5 years after irradiation. The maximum grade of toxicity will be determined for each patient.

The Common Terminology Criteria for Adverse Events V4.0 (CTCAE V4.0) will be used to grade acute toxicity from radiation therapy. The criteria are relevant from the 8th irradiation day until day 90, i.e. until the 1st follow-up visit. Thereafter, the RTOG/EORTC Criteria of Late Effects will be utilized. All acute radiation effects will be documented on an Acute Radiation Effect-Form. In addition, the AE-Form and/or SAE-Form will be filled out.

RTOG/EORTC Late Morbidity 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 radiation effects will be documented on a Late Radiation Effect-Form. Every patient will be followed for LPFS and AEs for a time period of 5 years. Furthermore, patients will be followed for survival and locoregional recurrences for a time period of 5 years after completion of the irradiation.

Accrual period for the trial will be approximately 7 years starting in autumn 2010.

The individual reasons for the study interruption are patient death or the withdrawal of the patient to participate in the study. 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.

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 appropriate therapy or inclusion in other investigative protocols, but should still be followed in order to document survival and radiation specific AEs.

High incidence of unknown AEs or increase in known AEs with the disadvantageous proportion between risk and benefits of the proposed radiation therapy or unacceptable high rates of SAEs can terminate the study earlier.

This trial is a phase III study to demonstrate that ion radiotherapy (experimental treatment) is not relevantly inferior to proton radiotherapy (standard treatment) with respect to the 5 year LPFS rate. The null-hypothesis to be assessed in confirmatory analysis states that the 5 year LPFS rate in the experimental treatment group is at least 5% lower than the 5 year LPFS rate in the standard treatment group. Confirmatory analysis for the primary end point is based on the intention-to-treat population. A group-sequential design is applied with one interim analysis after half of the expected number of events has occurred to allow for an early stopping of the study in case of an overwhelming treatment effect. The stopping rule is according to O'Brien and Fleming [18]. The one-sided critical level in the interim analysis is given by 0.26%, and in the final analysis it is given by 2.4%. Test decision is made by comparing the corresponding repeated confidence intervals to the boundary of the non-inferiority range of -5% (LPFS rate experimental treatment - LPFS rate standard treatment). With this design, the one-sided overall type I error rate is controlled by 2.5%. The confidence intervals for the differences between the LPFS rates are calculated based on the log(-log)-transformed Kaplan-Meier estimates of the rates using Greenwood's formula to estimate the underlying variance [19].

The total sample size of 154 patients provides a power of 80% to show non-inferiority of the experimental treatment to the standard treatment if the experimental treatment is in fact superior with respect to the 5 year LPFS rate by 7% and if the LPFS rate of the standard treatment group is 90%. Calculation of the sample size is based on the non-inferiority test for the differences between rates as described by Farrington and Manning [20].

If the confirmatory aim of the study cannot be reached, the trial still allows a descriptive head-to-head comparison of the two treatments, and the inspection of the confidence interval for the treatment effect enables to exclude a certain amount of difference in efficacy between the treatments.

To assess the impact of major protocol deviations, an analogous analysis of the primary outcome variable will be performed for the per protocol set. Analysis of the secondary endpoints as overall survival, progression-free and metastasis-free survival will be performed analogously to the primary endpoint. The survival curves will be estimated using the Kaplan-Meier product-limit method [21].

All documented variables will be analyzed descriptively by tabulation of the measures of the empirical distributions according to the scale level of the variables. Descriptive p-values of the corresponding statistical tests comparing the treatment groups and associated 95% confidence intervals will be given. The homogeneity of the treatment groups will be described by comparison of the demographic data and the baseline values of the measured variables.

Safety analysis and analysis of toxicity will be based on the data set of all randomized patients who were treated with the experimental or the standard treatment at least once. The safety analysis includes calculation and comparison of frequencies and rates of adverse and serious adverse events reported in the two treatment groups.

All analyses will be done using SAS version 9.1 or higher.

Proton therapy is the standard treatment option in skull base chondrosarcoma patients after the tumour resection. Our experience with carbon ion therapy in patients with chondrosarcomas showed excellent results. However, until now, it has been not possible to compare both particles, i.e. protons and carbon ions, directly within the same facility for 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 due to the reduced lateral scattering of the carbon beam.