Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial

Abstract

BackgroundTreatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.First Japanese Data on the evaluation of carbon ion radiation therapy for the treatment of primary high-grade gliomas showed promising results in a small and heterogeneous patient collective.Methods DesignIn the current Phase I/II-CINDERELLA-trial re-irradiation using carbon ions will be compared to FSRT applied to the area of contrast enhancement representing high-grade tumor areas in patients with recurrent gliomas. Within the Phase I Part of the trial, the Recommended Dose (RD) of carbon ion radiotherapy will be determined in a dose escalation scheme. In the subsequent randomized Phase II part, the RD will be evaluated in the experimental arm, compared to the standard arm, FSRT with a total dose of 36 Gy in single doses of 2 Gy.Primary endpoint of the Phase I part is toxicity. Primary endpoint of the randomized part II is survival after re-irradiation at 12 months, secondary endpoint is progression-free survival.DiscussionThe Cinderella trial is the first study to evaluate carbon ion radiotherapy for recurrent gliomas, and to compare this treatment to photon FSRT in a randomized setting using an ion beam delivered by intensity modulated rasterscanning.Trial RegistrationNCT01166308

External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain

“…An interesting study has started at the Ion Therapy Center and the University Hospital in Heidelberg (Germany). In the Phase I/II CINDERELLA trial, re-irradiation using carbon ions is compared to FSRT applied to the area of contrast enhancement representing high-grade tumour areas in patients with recurrent gliomas [46]. In Phase I, the recommended dose of carbon ion radiotherapy will be determined in a dose escalation scheme.…”

Clinical Evidence and Radiobiological Background of Particle Radiation Therapy

“…Most of the patients in fact already received a full course of radiotherapy, for this reason a further reirradiation programme has to be applied cautiously [ 62 ].…”

“…Toxicity is the primary endpoint of phase I, for phase II instead it is the 12-months survival after reirradiation while the secondary endpoint is the PFS. The most important inclusion criteria are the unifocal, supratentorial, recurrent glioma, the contrast enhancement on T1-weighted MRI and/ or Amino-Acid-PET-positive high-grade tumour areas, indication for reirradiation, an age above 18 years and the Karnofsky performance score more or equal to 60 [ 62 ].…”

“…The standard protocol instead is applied using a proton boost up to 10 GyE in fi ve single fractions of 2 GyE each. The endpoints are the OS as well as the PFS [ 62 ].…”

Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs

“…Clinical trials are ongoing that evaluate dose escalation with protons or carbon. 95,96 RADIOIMMUNOTHERAPY Antibodies and radionuclides Radioimmunotherapy (RIT) with monoclonal antibodies (mAb) labelled with therapeutic radionuclides are promising candidates to be applied alone or in combination with radio(chemo)therapy to improve treatment outcomes. The application of mAb is restricted by factors such as the high interstitial pressure inside the tumour, limited blood supply, inhomogeneous or inconstant expression of antigens, necrosis or fibrosis as physiological barriers, formation of immune complexes, catabolism of immunoglobulins, the blood-brain barrier and possible unfavourable biodistribution of the mAb leading to radiation burden in normal tissue.…”