A step towards international prospective trials in carbon ion radiotherapy: investigation of factors influencing dose distribution in the facilities in operation based on a case of skull base chordoma

In this framework, ULICE was a FP7 project (part of ENLIGHT) initiated in 2009 to address specific issues such as particle radiobiology, intra-fractional moving targets, adaptive treatment planning, database organization and gantry engineering [11]. In particular, ULICE-WP2 aimed to adapt joint concepts for dose volume and outcome assessment, standard operating procedures for clinical trial design and a clinical research infrastructure.

The objective of our study was to describe and compare each stage of the treatment process in the existing CIRT centers worldwide illustrated in a case of skull base chordoma (SBC).

SBC is a rare and slow growing malignancy arising from the remnants of the notochord, optimally managed with surgery and postoperative radiation [12]. SBC is one of the most consolidated indications of CIRT [13‐17].

According to Table 2B, different equipment has been set up in the successive facilities since 1994. In Japan, the two synchrotrons of the pilot Heavy Ion Medical Accelerator in Chiba (HIMAC) produce ion beams from ⁴He to ⁵⁴Xe up to a maximum energy of 800 MeV/u. PS was first implemented with a beam-wobbling and ridge filter delivery method. The same type of facility has been reproduced in Hyogo, Gunma and Tosu, making the PS delivery method the most widely used in the world so far (Table 2). At the same time, GSI reproduced and improved the ABS system originally outlined in the pioneer facility in Berkeley - standardizing the raster scanning delivery system in European then Chinese facilities. More recently the new HIMAC facility implemented a high dose rate ABS system incorporating superconducting technology, which offers fast 3D repainting as well as a reduced gantry.

Patient setup may interfere on intra/inter fraction tumor motion and the related CTV-PTV margin to apply (Table 2C).

Differences in equipment between centers may influence the components of the physical dose at the patient’s entrance.

It appears possible to accurately measure the physical dose and its composition in terms of individual particle energy, direction and LET spectrum at the exit of the delivery system. Such parameters in addition to their spatial distribution in relation with cross-section anatomy could be stored to feed more robust modeling systems in the future.

devices and the CIRT beam has to be emphasized as reported in our clinical model [45, 46]. Although they cannot easily be standardized, positioning systems and anatomic data acquisition (contrast medium use) must be perfectly described in the trial protocol as this could affect particle range calculation.

The GTV and CTV are oncological volumes defined in the dedicated ICRU Reports [4, 24‐28]. Contrarily to GTV, CTV delineation varies substantially between the centers. We could hold a joint symposium to adopt consensus delineation guidelines with standardized imaging procedures as performed in other tumor locations [47] - keeping in mind the natural history of the disease [48, 49].

Conversely to EBRT, adding internal and set-up margins quadratically to construct PTV [4] appears inadequate in CIRT since depth margins are to be incorporated to account for range uncertainties in addition to the typical lateral geometric uncertainties. When using a single beam, the different margins could theoretically combined as an anisotropic shell around the CTV [50]. Portal-specific PTV should be theoretically employed in PS. However, when two (or more) non-parallel opposed particle beams are applied, delineation of a (unique) PTV would generate complex computation issues for the TPS [26]. ABS raise additional issues. The dose is not prescribed to a reference point but to each voxel. Moreover, organ motion, artificial material and tissue heterogeneities may have a strong impact on dose distribution [51, 52]. Overall, specific attention and complex irradiation techniques such as gating, repainting and tracking are needed to alleviate the motion effect in CIRT although this factor is not in the foreground in SBC [53‐55].

The ICRU recommends that the absorbed dose distribution (3D) be systematically reported, to allow interpretation of the effects and to reconstruct the irradiation conditions if needed [27, 56]. However, specification of these quantities alone is not usually sufficient to predict biological effects when comparing treatments in different conditions. In CIRT the particle energy spectrum varies along the ion path within the treated volume. Each voxel receives a mixed field of particles of different LET and nature due to fragmentation, so the same physical dose at a given point may correspond to different particle spectra, each of which could lead to a particular biological and clinical effect [57].

Despite different specifications, EQD should be reported in addition to absorbed dose [10, 57‐59]. These two quantities are expressed in Gy. In order to avoid confusion, the symbol for EQD should be written “D (EQD)” with a space between “D” and “EQD”.

EQD is the product of absorbed dose and a transformation function (no dimension) which includes all the factors that influence the biological/medical effect(s) – including RBE [19] (Fig. 2). It is likely that the transformation functions are distinct between the centers and their determinants need thus to be reported.

In addition the calculation of EQD is not equivalent between the active facilities and comparing different TPS is a very difficult task in CIRT due to the many interconnected components and the different biological models [60].

Each individual TPS generate dose calculation uncertainties as soon the beam penetrates into the patient due to the modeling of mixed radiation field and tissue heterogeneities [61] (Fig. 3). Monte Carlo simulations are probably the most accurate and reliable to estimate those uncertainties [62]. NIRS estimated that EQDs produced at NIRS and GSI are biologically identical using HSG and in vivo assays [63]. CNAO thus recalculated their treatment plans - minimizing differences in physical dose distributions between the two treatment plans. FLUKA has been interfaced with LEM I to retrieve physical doses. Overall, the NIRS model estimates a lower RBE of carbon ions when compared to LEM. They proposed conversion tables to minimize the physical dose variations in the PTV [64‐66].

Alternative models particularly in the domain of nano- and microdosimetry could apply [67]. A model-independent interface for RBE predictions is being implemented [68].

So far, research in treatment planning of CIRT is usually based on a fixed RBE or α/β value. Since fractionation regimens differ from 3D-CRT, α/β ratios for dose-limiting toxicity and the specific tumor cell type are expected to differ substantially [69]. Radiobiological data for both human tumors and healthy tissues are incomplete. Ideally, prospective experiments should be performed. Overlapping of PTV and OAR raises additional issues [70].

Each center has developed its own quality assurance procedures based on local equipment and the available “homemade” measuring tools. When international clinical trials will be initiated, it will be critical to have a uniform quality assurance procedure.

ICRU/IAEA Committee Report 76 - which some of the members of our committee belonged to - proposed recommendations for harmonized dosimetry guidelines and accurate beam calibration [71].

Thereupon, ETOILE is the first transnational prospective randomized trial comparing definitive carbon ion therapy versus photon or combined photon and protontherapy as standard treatment for unresectable or macroscopically uncompleted resected radioresistant tumors. Eligible tumors are axial chordoma (except of base of skull), adenoid cystic carcinoma of head and neck (except of trachea) and sarcomas of any site (except chondrosarcoma of the skull base), non-previously irradiated and without pre-planned surgery or chemotherapy after the clinical trial procedure. Randomization is balanced 1 for 1. Patients of the experimental arm are treated in carbon ions centers in Europe and patients of the standard arm are treated in France in their closest participating radiotherapy center. An accrual of 250 patients is needed and an absolute difference of 20% of relapse free survival at five years is awaited. The main endpoint is the progression free survival at five years (ClinicalTrials.​gov Identifier: NCT02838602) We applied the aforementioned proposals when we drafted the protocol [72].