The treatment planning for proton radiotherapy involves some challenges not encountered in photon radiotherapy planning. First, one must define the proximal as well as the distal edge of the beam accurately. When using the more common “passively scattered” proton beam, one creates a distal edge of the beam through the use of compensators, which are unique for each beam used for treatment. These compensators must account for target motion, daily set-up error, and the range uncertainty of protons; this is achieved via the use of a “smearing” algorithm. Although smearing ensures coverage of the distal extent of the tumor along the path of the beam regardless of daily variation, this leads to a significant volume of normal tissue beyond the distal extent of the target being treated unnecessarily.
While these challenges with target motion and daily set-up error are present even in photon radiotherapy planning, range uncertainty is a unique problem encountered with proton radiotherapy planning. Uncertainties in the range of the proton beam are a result of greater attenuation of the beam by higher density structures in its path and the consequent, greater sensitivity of proton beams to tissue inhomogeneity than traditional photon beams. In practice, these range uncertainties originate from computed tomography (CT) artifacts, errors in converting CT Hounsfield units to proton stopping power, changes in patient geometry during treatment, and changes in tissue density along the beam path, especially when the beam traverses a loop of bowel with variable amount of air, a high-density rib that moves during breathing, or a sliver of lung tissue that expands and contracts with respiration. In turn, this range uncertainty may result in unexpected areas of under- or over-dosage within the treatment volume and also in adjacent normal structures if the actual proton range is different from that assumed during treatment plan optimization. This range uncertainty presents much less of an issue for liver tumors than other disease sites because beams can be chosen such that they traverse through uniform density of liver tissue to reach the tumor and because there is little opportunity for large changes in the structures in the beam path after the time of simulation, at least from the standpoint of their relative density. By the same token, though, restricting beam angles to those that traverse entirely through liver tissue and those that do not stop directlyin front of a critical normal structure (see below), does pose some limits on the degree of conformality achievable with proton therapy. Lastly, when using passive scatter technology, there is currently no method to conform the dose to the proximal extent of the target.
Many of these difficulties can be at least partially surmounted via the use of “spot scanning” proton radiotherapy. In this technique, magnetic beam scanning technology is used to place individual Bragg peaks within small areas of the target, similar to a pixelated image. Taken together, these “spots” encompass the whole of the target volume and, thus, allows for conformality, especially to the distal extent of the target. This technique also permits modulation of the delivered dose within a target, in essence, achieving intensity modulated proton radiotherapy.
With both passively scattered and spot scanned proton beams, the relative biological effectiveness (RBE) of protons as compared to photons is, by convention and consensus, assigned a value of 1.1 at most institutions. This means that a physical dose of 1 Gy delivered using proton radiotherapy is deemed biologically equivalent to 1.1 Gy delivered using photon radiotherapy, otherwise described as 1.1 CGE or Cobalt Gray Equivalent. This assignment of proton RBE of a value of 1.1 is controversial since it depends on the tissue in question, the choice of biological endpoints, the timing of assessment of these endpoints, and the clinical relevance of these endpoints7
. However, above and beyond this debate, there is some question of unpredictable variation of the RBE of the proton beam, particularly at the Bragg peak7, 8
. Due to this unpredictability and the issue of range uncertainty noted above, beams are often chosen such that they do not stop directlyin front of a critical normal structure such as the duodenum or the spinal cord.
The theoretical advantages of carbon ion therapy include all of those previously discussed with proton therapy with the added potential benefit of increased RBE. The increased RBE is generally attributed to the greater energy transferred per unit length of tissue along the ionization track (linear energy transfer, LET) track of the carbon ion beam. Generally, an RBE of 3 is used for planning with carbon ion therapy9
. However, in a recent review of calculated RBE values for carbon ion radiotherapy, the mean RBE was noted to be 2.2, with significant variability of this value based upon the model system used10
. Furthermore, it is thought that the RBE for carbon ion radiotherapy may vary considerably with the fractionation schedule used11
. Although, in theory, a high RBE could offer an advantage in regards to tumor kill, similar concerns regarding normal tissue toxicity remain. In addition to the benefits of a particle with finite particle range and higher RBE, another potential clinical advantage of carbon ions is the lower oxygen enhancement ratio (OER) due to their higher linear energy transfer (LET). Much of the work examining OER for carbon ion therapy has been performed in cultured cells, with estimates of an OER of around 2 compared to an OER of 3 for photon irradiation12
. In a pre-clinical tumor model, an OER for carbon ion therapy of 1.6 was seen, compared to 3.4 for photons13
. This decreased OER could lead to improved responses in hypoxic areas of HCC, which are more resistant to photon irradiation.
While not true in previous decades, proton radiotherapy is increasingly available to patients across the United States and globally. Since the initial conception of therapeutic proton radiotherapy in the 1940s and its clinical deployment for cancer treatment by investigators in Sweden, the Berkeley Radiation Laboratory and the Harvard Cyclotron laboratory in the following decade, nearly thirty proton radiotherapy facilities have been established worldwide with over 60,000 patients treated for a variety of malignancies14, 15
. Conversely, the facilities offering carbon ion therapy for HCC are extraordinarily limited, with the largest clinical treatment experience coming from the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan and more recent treatment facilities in Darmstadt and Heidelberg, Germany, and Hyogo, Japan.