cancers Review Carbon Ion Radiobiology Walter Tinganelli 1 and Marco Durante 1,2,* 1 Biophysics Department, GSI Helmholtzzentrum für Schwerionenforchung, Planckstraße 1, 64291 Darmstadt, Germany; [email protected] 2 Institut für Festkörperphysik, Technische Universität Darmstadt, Hochschulstraße 8, 64289 Darmstadt, Germany * Correspondence: [email protected]; Tel.: +49-6159-71-2009 Received: 22 September 2020; Accepted: 14 October 2020; Published: 17 October 2020 Simple Summary: Radiotherapy with carbon ions has been used for over 20 years in Asia and Europe and is now planned in the USA. The physics advantages of carbon ions compared to X-rays are similar to those of protons, but their radiobiological features are quite distinct and may lead to a breakthrough in the treatment of some cancers characterized by high mortality. Abstract: Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results. Keywords: carbon ions; particle therapy; radiotherapy; radiobiology; hypoxia; RBE; immunotherapy; metastasis 1. Introduction The interest in carbon ion radiobiology derives from the use of these nuclei in cancer radiotherapy. The original idea of Robert R. Wilson, a student of Ernest Orlando Lawrence at the University of California in Berkeley (CA, USA), was to exploit the Bragg peak to improve the dose-depth distribution in radiotherapy [1], and this can be done with fast protons. Using heavier ions in cancer therapy was proposed and pursued by Cornelius A. Tobias at the Lawrence Berkeley Laboratory (LBL) [2], with the idea that heavier ions have radiobiological properties that can lead to better results than X-rays or protons. The physical properties of heavy ions and protons are similar (Figure1)[ 3,4]. Heavy ions have reduced lateral scattering and longitudinal straggling compared to protons, but they present a tail of light fragments beyond the Bragg peak and, for very heavy ions, nuclear fragmentation causes a decrease of the dose in the plateau region, as is commonly observed in tests of shielding materials using very heavy ions at energies characteristic of the cosmic ray spectrum [5]. Cancers 2020, 12, 3022; doi:10.3390/cancers12103022 www.mdpi.com/journal/cancers CancersCancers2020 2020, ,12 12,, 3022 3022 2 of2 of39 37 A B FigureFigure 1.1. PhysicalPhysical properties properties of ofcarbon carbon ions ions in comparison in comparison to X- torays, X-rays, protons, protons, and helium and helium ions. (A ions.). (ADepth). Depth-dose-dose distributions distributions showing showing the theBragg Bragg peak peak for forall allions ions at the at the same same range, range, and and the the reduced reduced stragglingstraggling ofof heavierheavier ions.ions. ( B)).. Lateral Lateral scattering scattering is is reduced reduced by by increasing increasing the the ion ion mass. mass. However,However, thethe relativerelative biological effectiveness effectiveness (RBE) (RBE) increases increases with with the the radiation radiation linear linear energy energy 2 β2 transfertransfer (LET) (LET) [[66––1010]],, andand becausebecause the LET is proportional proportional to to z z2// 2 (where(where z zis isthe the ion ion effective effective charge charge andandβ itsits relativerelative velocity), velocity), fast fast ions ions (in (in the the entrance entrance channel) channel) will will have have a lower a lower RBE RBE than than slow slow ions ionsin inthe the target target region. region. Other Other biological biological effects eff ectsof high of high-LET-LET ions, ions, such suchas the as reduced the reduced dependence dependence on onfractionation fractionation and and cell cell-cycle-cycle stage, stage, and and especially especially the the reduced reduced oxygen oxygen enhancement enhancement factor factor (OER), (OER), mademade them them attractive attractive for for treatment treatment ofradioresistant of radioresistant malignancies malignancies (Figure (Figure2)[ 11 ,212) ].[11,12] Patients. Patients in Berkeley in wereBerkeley treated were in treated the period in the 1975–1992 period 197 with5–1992 several with ions:several He, ions: N, He, O, C,N, Ne,O, C, Si, Ne, and Si Ar, and [13 Ar]. 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However, entrance the LET entrance of heavy LET ions of heavy is relatively ions high,is relatively resulting high, in unacceptableresulting in unacceptable patient toxicities. patient Carbon toxicities. represents Carbon arepresents good compromise, a good compromise, with an LET inwith the an entrance LET in channel the entrance between channel 11 and between 13 keV 11/µ m,and and 13 akeV/μm, fairly high and LET a fairly on the high Spread-out-Bragg-peak LET on the Spread- (SOBP)out-Bragg between-peak 40-80(SOBP) keV between/µm (Figure 40-803 keV/μm)[ 15]. For (Figure this very 3) [15] reason,. For this Hirohiko very reason, Tsujii and Hirohiko his colleagues Tsujii atand the his National colleagues Institute at the ofNational Radiological Institute Sciences of Radiological (NIRS) inSciences Chiba, (NIRS) Japan i (nown Chiba, re-named Japan (now National re- Institutenamed National for Quantum Institute and for Radiological Quantum and Science Radiological and Technology) Science and elected Technology) to use 12C-ions elected for to therapyuse 12C- in 1994.ions for They therapy have nowin 1994. treated They overhave13,000 now treated patients over with 13,000 carbon patients ions with [16,17 carbon], by far ions the [16,17] largest, by cohort far worldwidethe largest withcohort these worldwide ions, and with their these success ions, and inspired their Gerhardsuccess inspired Kraft to Gerhard start a clinicalKraft to trial start with a C-ionsclinical at trial the GSIwith Helmholtzzentrum C-ions at the GSI Helmholtz für Schwerionenforschungzentrum für Schweri [18,19onenforschung], followed by [18,19] clinical, followed projects in dibyff erentclinical European projects countriesin different [20 European]. countries [20]. According to the Particle therapy co-operative Group (PTCOG) (https://www.ptcog.ch/) database, by the end of 2018 there were eight C-ion centers in Asia and four in Europe that have treated approximately 28,000 patients, and eight more centers are under construction or in the planning stage. Mayo Clinics in Jacksonville (FL, USA) has advanced plans for building the first C-ion therapy center in the USA [21]. This facility would mark a much-awaited return of heavy ion therapy in the USA after the end of the LBL pilot trial. Concerns with respect to the cost effectiveness and lack of FDA certification and approved reimbursement have hampered its introduction in the US so far [22]. The high investment cost is also affecting the well-established proton therapy [23], but the carbon cost is even higher, causing resilience even in the proton therapy community [24]. Yet some of the clinical results with C-ions, such as the long-term survival of chordoma patients in Germany [25] and locally advanced pancreatic cancer [26,27] and locally recurrent rectal cancer [28] in Japan, are clearly superior to both X-rays and protons [29]. This has triggered interest in international comparative trials with C-ions (Table1) and investments in pre-clinical radiobiological research also in USA, resulting in recent P20 (https://grants.nih.gov/grants/guide/pa-files/PAR-13-371.html) and R01 Cancers 2020, 12, 3022 3 of 37 (https:Cancers//grants.nih.gov 2020, 12, 3022 /grants/guide/rfa-files/RFA-CA-20-032.html) NCI grants on planning3 of a39 C-ion facility and radiobiology research. Cancers 2020, 12, 3022 3 of 39 1.2 Tumor e 1.0 s 1.2 o Tumor d 0.8 e e 1.0 s v o i t d 0.6 0N.8 ormal tissue C-ions a e l v e i 0.4 t 0.6 C-ions R Normal tissue a l e 0.4 0.2 R 0.0 0.2 0 50 100 150 200 0.0 0 D50epth (m10m0 ) 150 200 Depth (mm) Energy high low X-rays Energy high low Potential advantages X-rays LET low high