The more important heavy charged particle radiotherapy of the future is more likely to be with heavy ions rather than protons

Arguing against the Proposition is Alfred R. Smith, Ph.D. Dr. Smith obtained his Ph.D. in Physics from Texas Tech University, Lubbock, TX, in 1970. After completing a Postdoctoral Fellowship in Medical Physics at The University of Texas, M. D. Anderson Hospital and Tumor Institute, he held faculty positions at several institutions until he moved back to M. D. Anderson in 2002 as a Full Professor and Director of Proton Therapy Development, a position he held until 2010. Dr. Smith is a Fellow of the AAPM and the ACMP. His most recent major research interest has been in proton therapy, although over the years he has published extensively on other exotic forms of therapy such as neutrons, pions, and Cf-252 brachytherapy, for which he has published over 80 papers. With respect to their physical properties, heavier ions can do everything that can be done with protons, but better. With respect to biology, heavier ions have the potential to significantly improve clinical results at least for selected indications, including especially hypoxic tumors. Ions heavier than protons provide superior physical dose distributions due to reduced lateral scattering, reduced range straggling, and an increased ratio of dose in the target relative to the entrance region.1 In this regard, helium ions could replace protons leading to improved dose conformation at a comparable technical complexity (i.e., price) while maintaining biological properties comparable to those of protons.2,3 Another physical aspect is connected with accurate targeting. In many cases, the clinical advantage of ions may be seriously limited if the range cannot be controlled accurately, e.g., in the presence of heterogeneous tissues, setup errors, or organ motion. The related uncertainties largely prevent beam directions with organs at risk directly behind the Bragg-peak. In some clinical cases, the use of ions may, in fact, be inferior to modern photon techniques, as the latter are much more robust against these uncertainties. This is, of course, a common problem of heavy charged particles and challenges the often stated superiority of ions over photons. Heavier ions, however, offer some possibilities to measure the range in vivo and thus to verify accurate positioning of the Bragg-peak. These in vivo measurements make use of tissue activation,4 radioactive beams, or prompt secondary particles produced in nuclear reactions, and are not feasible with protons.5,6 The most important rationale for heavier ions, however, originates from the biology of high-LET radiation.7,8 This is the increased RBE in the tumor relative to the normal tissue and the increased effectiveness in hypoxic tumors.9 Probably not all patients will benefit from this, but for some dedicated indications, especially when highly resistant tumors and hypoxia are involved, this may make a great difference. Currently, evidence for the clinical benefit of high-LET radiation is still lacking and the necessary clinical trials are just being initiated. But even if this biological advantage would finally not be significant, the physical advantages remain and, leaving aside financial considerations, heavier ions would be the modality of choice in the future. Finally, the clinical benefit resulting from the dose sparing potential of protons relative to photons may in some cases be too small to justify the additional costs for proton facilities in the long term. This is especially the case in view of the enormous and still ongoing improvements achieved in photon RT. In conclusion, I think that both the substantial physical and biological potential of heavier ions will make them more important in the future than protons: more important in terms of clinical research opportunities and more important for some patients with tumors which cannot be cured with low-LET radiation. I will use the term “carbon ions” here as a surrogate for high-LET charged particles; they are the only high-LET charged particles to be used extensively in clinical investigations. Clinically, protons are considered to be low-LET particles. Carbon ions and protons have similar physical dose distributions; however, carbon ions have a presumed biological advantage arising from high-LET, which leads to higher RBE and lower OER. The rationale for carbon therapy is based on the hypothesis that high-LET carbon ions are more effective in killing oxygen-deficient tumor cells that are radioresistant to low-LET photons and protons. High-LET biological effects are complex, depending on a number of treatment and tissue factors and will not be discussed here.1,10 Carbon ion facilities cost ∼2–3 times more than proton facilities. Due to the large size and cost of isocentric gantries for carbon therapy, most treatments have been given with fixed beams having less clinical flexibility than isocentric gantries. Large uncertainties in the RBE in the carbon spread-out Bragg peak (SOBP) (∼1.5–3.4) can result in large variations in the delivered biological dose in the target volume. RBE values for normal and tumor tissues are not well known for protons or carbon ions.10 Carbon ions, due to their high/variable RBE, have the potential for increased risk of normal tissue damage.10 Due to fractionation effects, tumor cells that are initially oxygen-depleted may reoxygenate during a course of proton treatment—this may diminish/eliminate the hypothesized advantage of carbon ions. Carbon ion depth-dose distributions exhibit a “tail” of particle fragments created by fragmentation of carbon ions in the primary beam due to nuclear interactions. This tail contains high-LET components and continues for a distance (depending on initial ion energy) into normal tissues distal to the target volume.1 Proton beams do not have a tail in their dose distribution.10 The theoretical advantages of carbon ions over protons have not been proven in a clinical setting. Studies performed this far have shown an approximate equivalence of both modalities.1,10–12 In the USA, there is no FDA certification; there are no approved treatment procedure codes; and there is no approved reimbursement for carbon ion therapy. Modern proton therapy systems have substantially reduced the cost of proton facilities. Small hospitals/cancer centers and large clinical practices are now able to provide proton therapy; the growth curve for new facilities is steep. This situation is opposite for carbon ions: Carbon ions are biologically complex; facilities are too expensive; and there are too few facilities to conduct proton vs carbon prospective and randomized clinical trials required to compare the two modalities. Extremely high costs and the lack of data showing clinical superiority are major deterrents for carbon therapy. It is highly unlikely that carbon ions will replace protons in cancer treatment. My opponent points out several problems for carbon ion therapy: higher costs, lack of evidence, lack of gantries, and large RBE uncertainties. All these arguments are valid, but I think they all hold likewise against protons and they conceal the potential of heavier ions. The lack of FDA approval and reimbursement and unrealistic costs for carbon therapy may be specific to the USA (the average reimbursement in the USA for protons is $36k vs €19k for carbon in Europe) so cost may not hinder the development of ion therapy elsewhere. While technology is likely to reduce the cost for carbon ions in the future, both modalities will remain costly. These costs may be worthwhile if a clinical benefit can be gained. The lack of clinical evidence is, of course, as critical for protons as it is for carbon: a recent critical review of proton therapy for brain tumors showed that, despite reduced integral doses, no reduction of adverse events could be demonstrated.13 Also, the ASTRO Emerging Technology Committee concluded that further clinical research is needed.14 One reason may be biology: while the variable RBE is modeled in detail for ions, the simplification of proton RBE as commonly used in clinics may be associated with substantial uncertainties. The FDA approval of protons in the US facilitated clinical application but may have reduced the urge for clinical trials. Also, commercial interest resulted in the development of some low-cost solutions for protons which may not allow for the highest treatment quality. Some proton vendors even sacrificed gantries, which have just been introduced successfully for carbon. There will soon be 10 carbon facilities in operation in Asia and Europe,15 which will give ample possibilities for clinical trials. Currently, ion therapy relates to carbon only but it may turn out that other ions can do better for specific indications, be it due to physics or biology. Anything that protons can do, heavier ions can do better! It is our task to continue exploring the full clinical potential of heavy ions and not just the cheapest, easiest, but potentially least beneficial ion species. My colleague correctly states that heavy ions have sharper lateral penumbras than protons. They have higher charge, greater mass, and require higher energies per nucleon for the same range in tissue. Therefore, multiple Coulomb scattering of the primary beam is smaller for heavy ions than for protons.16 However, heavy ions have a “fragmentation tail” that penetrates beyond the range of the primary beam and this dose tail contains some relatively high RBE components. This unwanted/unnecessary dose must be explicitly included in treatment planning to avoid unanticipated “hot-spots” in adjacent normal tissues.16 For equivalent range in tissue, Bragg-peak dose distributions of proton and carbon beams show that protons have a lower relative entrance dose and stop at the end of their range without having a fragmentation tail. He also states that heavier ion ranges can be measured in vivo but fails to mention that such techniques, e.g., positron tomography, have been shown by many authors to be effective also for proton beams.17–19 The theoretical biological advantage offered by carbon ion beams is based on the existence of hypoxia in tumor cells and/or an increased RBE in the tumor relative to normal tissues. To date, this potential advantage has not been demonstrated in clinical studies; in fact, studies have shown a relative equivalence in clinical results from proton and carbon ion treatments.16–19 My colleague correctly states that, “Currently, evidence for the clinical benefit of high-LET radiation is still lacking …” and yet he concludes, “… and leaving aside financial considerations, heavier ions would be the modality of choice in the future.” This is not logical; if there is no demonstrated clinical benefit and the cost differential is quite large, the conclusion that heavier ions would be the modality of choice in the future is unfounded.