In 1994 a Phase I/II clinical study on carbon ion radiotherapy was begun at NIRS using HIMAC, which was then the world's only heavy ion accelerator complex dedicated to medical use in a hospital environment. Among several types of ion species, we have chosen carbon ions for cancer therapy because they had the most optimal properties in terms of possessing, both physically and biologically, the most effective dose-localization in the body. The purpose of the clinical study was to investigate the efficacy of carbon ion radiotherapy against a variety of tumors as well as to develop effective techniques for delivering an efficient dose to the tumor. The RBE of carbon ions was estimated to be 2.0 to 3.0 along the SOBP for acute skin reactions. As of August 2006, a total of 2,867 patients had been entered into Phase I/II or Phase II studies and analyzed for toxicity and local tumor response. The results have shown that carbon ion radiotherapy has the potential ability to provide a sufficient dose to the tumor with acceptable morbidity in the surrounding normal tissues. Tumors that appear to respond favorably to carbon ions include locally advanced tumors and those with histologically non-squamous cell type of tumors such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma, hepatoma, and bone/soft tissue sarcoma. By taking advantage of the biological and physical properties of high-LET radiation, the efficacy of treatment regimens with small fractions in short treatment times has been confirmed for almost all types of tumors in carbon ion radiotherapy.
Clinical trials of carbon radiotherapy started at HIMAC in 1994 using three treatment rooms and four beam ports, two horizontal and two vertical. The broad beam method was adopted to make a three-dimensionally uniform field at an isocenter. A spot beam extracted from an accelerator was laterally spread out by using a pair of wobbler magnets and a scatterer. A bar ridge filter modulated the beam energy to obtain the spread out Bragg peak (SOBP). The SOBP was designed to be flat in terms of the biological dose based on the consideration that the field consisted of various beams with different LET. Finally, the field of 20 cm in diameter with ± 2.5% uniformity was formed at the isocenter. The width of the maximum SOBP was 15 cm. When treating the lung or liver, organs that move due to breathing, the beam was irradiated only during the expiration period in a respiration-gated irradiation method. This reduced the treatment margin of the moving target. In order to prevent normal tissues adjacent to the target volume from irradiation by an unwanted dose, a layer-stacking method was developed. In this method, thin SOBP layers which have different ranges were piled up step by step from the distal end to the entrance of the target volume. At the same time, a multi-leaf collimator was used to change the aperture shape to match the shape of each layer to the cross-sectional shape of the target. This method has been applied to rather large volume cancers including bone and soft-tissue cancers. Only a few serious problems in the irradiation systems have been encountered since the beginning of the clinical trials. Overall the systems have been working stably and reliably.
This paper reviews the European activities in the field of tumour therapy with beams which have a Radio Biological Effectiveness (RBE) larger than 1. Initially neutron beams have been used. Then charged pions promised better cure rates so that their use was pursued in the framework of the `Piotron' project at the Paul Scherrer Institute (Switzerland). However both approaches did not meet the expectations and in the 80s the EULIMA project became the flagship of these attempts to improve the effects of the delivery of radiation doses of large RBE with respect to photons, electrons and even protons. The EULIMA ion accelerator was never built and it took more than ten years to see the approval, in Heidelberg and Pavia, of the construction of the HIT and CNAO `dual' centres for carbon ions and protons. In 2008 they will start treating patients. The developments that brought to these construction projects are described together with the special features of these two facilities. The third European dual centre is being built by Siemens Medical Systems in Marburg, Germany, while other facilities have been approved but not yet fully financed in Wiener Neustadt (Austria), Lyon (France) and Uppsala (Sweden). Finally the collaboration activities of the European Network ENLIGHT are presented together with the recent involvements of European industries in the construction of turn-key dual centres and the development of a new accelerator concept for hadrontherapy, the `cyclinac'.
The first clinical trial with carbon beams generated from HIMAC was conducted in June 1994. The total number of patients treated as of December 2006 was in excess of 3,000. In view of the significant growth in the number of protocols, the Japanese government gave its approval for carbon-ion therapy at NIRS as an advanced medical technology in 2003. The impressive advances of carbon-ion therapy using HIMAC have been supported by high-reliability operation and by advanced developments of beam-delivery and accelerator technologies. Based on our ten years of experience with HIMAC, we recently proposed a new accelerator facility for cancer therapy with carbon ions for widespread use in Japan. The key technologies of the accelerator and beam-delivery systems for this proposed facility have been under development since April 2004, with the main thrust being focused on downsizing the facility for cost reduction. Based on the design and R&D studies for the proposed facility, its construction was begun at Gunma University in April 2006. In addition, our future plans for HIMAC also include the design of a new treatment facility. The design work has already been initiated, and will lead to the further development of therapy using HIMAC. The following descriptions give a summary account of the new accelerator facility for cancer therapy with carbon ions and of the new treatment facility at HIMAC.
Gated radiation therapy is a promising method for improving the dose conformality of treatments to moving targets and reducing the total volume of irradiated tissue. Target motion is of particular concern in proton beam radiotherapy, due to the finite range of proton dose deposition in tissue. Gating allows one to reduce the extent of variation, due to respiration, of the radiological depth to target during treatment delivery. However, respiratory surrogates typically used for gating do not always accurately reflect the position of the internal target. For instance, a phase delay often exists between the internal motion and the motion of the surrogate. Another phenomenon, baseline drifting refers to a gradual change in the exhale position over time, which generally affects the external and internal markers differently. This study examines the influence of these two physiological phenomena on gated radiotherapy using an external surrogate.
In external beam radiotherapy, modern technologies for dynamic dose delivery and beam conformation provide high selectivity in radiation dose administration to the pathological volume. A comparable accuracy level is needed in the 3-D localization of tumor and organs at risk (OARs), in order to accomplish the planned dose distribution in the reality of each irradiation session. In-room imaging techniques for patient setup verification and tumor targeting may benefit of the combined daily use of optical tracking technologies, supported by techniques for the detection and compensation of organ motion events. Multiple solutions to enhance the use of optical tracking for the on-line correction of target localization uncertainties are described, with specific emphasis on the compensation of setup errors, breathing movements and non-rigid deformations. The final goal is the implementation of customized protocols where appropriate external landmarks, to be tracked in real-time by means of non-invasive optical devices, are selected as a function of inner target localization. The presented methodology features high accuracy in patient setup optimization, also providing a valuable tool for on-line patient surveillance, taking into account both breathing and deformation effects. The methodic application of optical tracking is put forward to represent a reliable and low cost procedure for the reduction of safety margins, once the patient-specific correlation between external landmarks and inner structures has been established. Therefore, the integration of optical tracking with in-room imaging devices is proposed as a way to gain higher confidence in the framework of Image Guided Radiation Therapy (IGRT) treatments.
Charged particle therapy depends on biological information for the dose prescription. Relative biological effectiveness or RBE for this requirement could basically be provided by experimental data. As RBE values of protons and carbon ions depend on several factors such as cell/tissue type, biological endpoint, dose and fractionation schedule, a single RBE value could not deal with all different radiosensitivities. However, any biological model with accurate reproducibility is useful for comparing biological effectiveness between different facilities. We used mouse gut crypt survivals as endpoint, and compared the cell killing efficiency of proton beams at three Japanese facilities. Three Linac X-ray machines with 4 and 6 MeV were used as reference beams, and there was only a small variation (coefficient of variance < 2%) in biological effectiveness among them. The RBE values of protons relative to Linac X-rays ranged from 1.0 to 1.11 at the middle of a 6-cm SOBP (spread-out Bragg peak) and from 0.96 to 1.01 at the entrance plateau. The coefficient of variance for protons ranged between 4.0 and 5.1%. The biological comparison of carbon ions showed fairly good agreement in that the difference in biological effectiveness between NIRS/HIMAC and GSI/SIS was 1% for three positions within the 6-cm SOBP. The coefficient of variance was < 1.7, < 0.6 and < 1.6% for proximal, middle and distal SOBP, respectively. We conclude that the inter-institutional variation of biological effectiveness is smaller for carbon ions than protons, and that beam-spreading methods of carbon ions do not critically influence gut crypt survival.
The clinical dose distributions of therapeutic carbon beams, currently used at NIRS HIMAC, are based on in-vitro Human Salivary Gland (HSG) cell survival response and clinical experience from fast neutron radiotherapy. Moderate radiosensitivity of HSG cells is expected to be a typical response of tumours to carbon beams. At first, the biological dose distribution is designed so as to cause a flat biological effect on HSG cells in the spread-out Bragg peak (SOBP) region. Then, the entire biological dose distribution is evenly raised in order to attain a RBE (relative biological effectiveness) = 3.0 at a depth where dose-averaged LET (linear energy transfer) is 80 keV/μm. At that point, biological experiments have shown that carbon ions can be expected to have a biological effect identical to fast neutrons, which showed a clinical RBE of 3.0 for fast neutron radiotherapy at NIRS. The resulting clinical dose distribution in this approximation is not dependent on dose level, tumour type or fractionation scheme and thus reduces the unknown parameters in the analysis of the clinical results. The width SOBP and the clinical / physical dose at the center of SOBP specify the dose distribution. The clinical results analysed in terms of TCP were found to show good agreement with the expected RBE value at higher TCP levels. The TCP analysis method was applied for the prospective dose estimation of hypofractionation.
There are currently no guidelines for prescribing and reporting radiation therapy (RT) with ion beams. In this paper an overview over some technical aspects and their implication on ion RT are reported. This includes a discussion of the difference in the treatment planning systems currently used for active and passive beam shaping systems, aspects of patient positioning and target definition and dose prescription. Special emphasis is put on the questions arising from the use of the beam scanning methods in combination with biological treatment plan optimization, which is used in the German heavy ion therapy facility at GSI and will also be introduced at the hospital based facility in Heidelberg. Furthermore, the Heidelberg approach for the clinical dose prescription is compared with the methods developed at HIMAC in Chiba, Japan.
Due to the RBE variations, the carbon-ion doses (in Gy) are no longer sufficient to monitor adequately the biological effect of these radiations. Therefore, "RBE dose weighting factors" - WRBE - allowing for the RBE variations with energy, dose and biological system have to be introduced in the treatment plans in order to provide the physician with interpretable information. This paper compares the methods employed for this purpose at NIRS and GSI, which are specific of the beam delivery system of these institutions. NIRS has a "passive" beam delivery system where the dose distribution in the SOBP is determined by a Ridge filter. The dose distribution - and thus, the shaping of the filter - is chosen according to the clinical situation and determined with respect to WRBE factors in order to yield a biologically iso-effective SOBP. WRBE factors in the SOBP are at first derived from a RBE/LET function for HSG cells, then normalized to 3 at a LET of 80 keV/μm. The latter value of 3 corresponds to the clinical RBE of NIRS-neutrons, which were found to exhibit the same radiobiological properties as 80 keV/μm carbon-ions. GSI has a "dynamic" beam delivery system ("spot" or "voxel" scanning) making it possible to irradiate irregular volumes and to modulate the radiation intensity according to the radiosensitivity of different tissues and/or different sub-volumes. Due to the "power" and the resulting complexity of the system, WRBE factors are determined through an integrated calculation code allowing iterative interaction of both physical and radiobiological parameters. The "Local Effect Model" (LEM) was developed in this view with the aim of deriving carbon-ion WRBE factors from the parameters determining the response to photons. Advantages and weaknesses of the respective methods will be discussed.