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Published in: Radiation Oncology 1/2018

Open Access 01-12-2018 | Review

New insights in the relative radiobiological effectiveness of proton irradiation

Authors: K. Ilicic, S. E. Combs, T. E. Schmid

Published in: Radiation Oncology | Issue 1/2018

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Abstract

Background

Proton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inverted depth-dose profile. The sparing of normal tissue has additional advantages in the treatment of pediatric patients, in whom the risk of secondary cancers and late morbidity is significantly higher. Up to date, a fixed relative biological effectiveness (RBE) of 1.1 is commonly implemented in treatment planning systems with protons in order to correct the physical dose. This value of 1.1 comes from averaging the results of numerous in vitro experiments, mostly conducted in the middle of the spread-out Bragg peak, where RBE is relatively constant. However, the use of a constant RBE value disregards the experimental evidence which clearly demonstrates complex RBE dependency on dose, cell- or tissue type, linear energy transfer and biological endpoints. In recent years, several in vitro studies indicate variations in RBE of protons which translate to an uncertainty in the biological effective dose delivery to the patient. Particularly for regions surrounding the Bragg peak, the more localized pattern of energy deposition leads to more complex DNA lesions. These RBE variations of protons bring the validity of using a constant RBE into question.

Main body

This review analyzes how RBE depends on the dose, different biological endpoints and physical properties. Further, this review gives an overview of the new insights based on findings made during the last years investigating the variation of RBE with depth in the spread out Bragg peak and the underlying differences in radiation response on the molecular and cellular levels between proton and photon irradiation. Research groups such as the Klinische Forschergruppe Schwerionentherapie funded by the German Research Foundation (DFG, KFO 214) have included work on this topic and the present manuscript highlights parts of the preclinical work and summarizes the research activities in this context.

Short conclusion

In summary, there is an urgent need for more coordinated in vitro and in vivo experiments that concentrate on a realistic dose range of in clinically relevant tissues like lung or spinal cord.
Literature
1.
2.
go back to reference Durante M, Orecchia R, Loeffler JS. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat Rev Clin Oncol. 2017;14(8):483–95.CrossRefPubMed Durante M, Orecchia R, Loeffler JS. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat Rev Clin Oncol. 2017;14(8):483–95.CrossRefPubMed
3.
go back to reference Loeffler JS, Durante M. Charged particle therapy--optimization, challenges and future directions. Nat Rev Clin Oncol. 2013;10(7):411–24.CrossRefPubMed Loeffler JS, Durante M. Charged particle therapy--optimization, challenges and future directions. Nat Rev Clin Oncol. 2013;10(7):411–24.CrossRefPubMed
4.
go back to reference Alan Mitteer R, et al. Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species. Sci Rep. 2015;5:13961.CrossRefPubMedPubMedCentral Alan Mitteer R, et al. Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species. Sci Rep. 2015;5:13961.CrossRefPubMedPubMedCentral
6.
go back to reference Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol. 1999;50(2):135–42.CrossRefPubMed Gerweck LE, Kozin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol. 1999;50(2):135–42.CrossRefPubMed
7.
go back to reference Paganetti H. Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol. 2014;59(22):R419–72.CrossRefPubMed Paganetti H. Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol. 2014;59(22):R419–72.CrossRefPubMed
8.
go back to reference Gudjonsson O, et al. Stereotactic irradiation of skull base meningiomas with high energy protons. Acta Neurochir. 1999;141(9):933–40.CrossRefPubMed Gudjonsson O, et al. Stereotactic irradiation of skull base meningiomas with high energy protons. Acta Neurochir. 1999;141(9):933–40.CrossRefPubMed
9.
go back to reference Chang JY, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer. 2011;117(20):4707–13.CrossRefPubMedPubMedCentral Chang JY, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer. 2011;117(20):4707–13.CrossRefPubMedPubMedCentral
10.
go back to reference Britten RA, et al. Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam. Radiat Res. 2013;179(1):21–8.CrossRefPubMed Britten RA, et al. Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam. Radiat Res. 2013;179(1):21–8.CrossRefPubMed
11.
go back to reference Chaudhary P, et al. Relative biological effectiveness variation along monoenergetic and modulated Bragg peaks of a 62-MeV therapeutic proton beam: a preclinical assessment. Int J Radiat Oncol Biol Phys. 2014;90(1):27–35.CrossRefPubMed Chaudhary P, et al. Relative biological effectiveness variation along monoenergetic and modulated Bragg peaks of a 62-MeV therapeutic proton beam: a preclinical assessment. Int J Radiat Oncol Biol Phys. 2014;90(1):27–35.CrossRefPubMed
12.
go back to reference Cuaron JJ, et al. Exponential increase in relative biological effectiveness along distal edge of a proton Bragg peak as measured by deoxyribonucleic acid double-strand breaks. Int J Radiat Oncol Biol Phys. 2016;95(1):62–9.CrossRefPubMedPubMedCentral Cuaron JJ, et al. Exponential increase in relative biological effectiveness along distal edge of a proton Bragg peak as measured by deoxyribonucleic acid double-strand breaks. Int J Radiat Oncol Biol Phys. 2016;95(1):62–9.CrossRefPubMedPubMedCentral
13.
14.
go back to reference IAEA. Relative Biological Effectiveness in Ion Beam Therapy, Technical Report Series, 2008, ISSN 0074–1914; no. 461. IAEA. Relative Biological Effectiveness in Ion Beam Therapy, Technical Report Series, 2008, ISSN 0074–1914; no. 461.
15.
go back to reference Finnberg N, et al. Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo. Cancer Biol Ther. 2008;7(12):2023–33.CrossRefPubMedPubMedCentral Finnberg N, et al. Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo. Cancer Biol Ther. 2008;7(12):2023–33.CrossRefPubMedPubMedCentral
16.
go back to reference Calugaru V, et al. Radiobiological characterization of two therapeutic proton beams with different initial energy spectra used at the Institut Curie Proton Therapy Center in Orsay. Int J Radiat Oncol Biol Phys. 2011;81(4):1136–43.CrossRefPubMed Calugaru V, et al. Radiobiological characterization of two therapeutic proton beams with different initial energy spectra used at the Institut Curie Proton Therapy Center in Orsay. Int J Radiat Oncol Biol Phys. 2011;81(4):1136–43.CrossRefPubMed
17.
go back to reference Hada M, Sutherland BM. Spectrum of complex DNA damages depends on the incident radiation. Radiat Res. 2006;165(2):223–30.CrossRefPubMed Hada M, Sutherland BM. Spectrum of complex DNA damages depends on the incident radiation. Radiat Res. 2006;165(2):223–30.CrossRefPubMed
18.
go back to reference Tommasino F, Durante M. Proton radiobiology. Cancers (Basel). 2015;7(1):353–81.CrossRef Tommasino F, Durante M. Proton radiobiology. Cancers (Basel). 2015;7(1):353–81.CrossRef
19.
go back to reference Grosse N, et al. Deficiency in homologous recombination renders mammalian cells more sensitive to proton versus photon irradiation. Int J Radiat Oncol Biol Phys. 2014;88(1):175–81.CrossRefPubMed Grosse N, et al. Deficiency in homologous recombination renders mammalian cells more sensitive to proton versus photon irradiation. Int J Radiat Oncol Biol Phys. 2014;88(1):175–81.CrossRefPubMed
20.
go back to reference Pietro DC, et al. Cellular and molecular effects of protons: apoptosis induction and potential implications for cancer therapy. Apoptosis. 2006;11:57.CrossRefPubMed Pietro DC, et al. Cellular and molecular effects of protons: apoptosis induction and potential implications for cancer therapy. Apoptosis. 2006;11:57.CrossRefPubMed
21.
go back to reference Manti L, et al. Measurements of metaphase and interphase chromosome aberrations transmitted through early cell replication rounds in human lymphocytes exposed to low-LET protons and high-LET 12C ions. Mutat Res. 2006;596(1–2):151–65.CrossRefPubMed Manti L, et al. Measurements of metaphase and interphase chromosome aberrations transmitted through early cell replication rounds in human lymphocytes exposed to low-LET protons and high-LET 12C ions. Mutat Res. 2006;596(1–2):151–65.CrossRefPubMed
22.
go back to reference Green LM, et al. Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution. Radiat Res. 2001;155(1 Pt 1):32–42.CrossRefPubMed Green LM, et al. Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution. Radiat Res. 2001;155(1 Pt 1):32–42.CrossRefPubMed
23.
go back to reference Goetz W, Morgan MN, Baulch JE. The effect of radiation quality on genomic DNA methylation profiles in irradiated human cell lines. Radiat Res. 2011;175(5):575–87.CrossRefPubMed Goetz W, Morgan MN, Baulch JE. The effect of radiation quality on genomic DNA methylation profiles in irradiated human cell lines. Radiat Res. 2011;175(5):575–87.CrossRefPubMed
24.
go back to reference Wouters BG, et al. Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital. Radiat Res. 2015;183(2):174–87.CrossRefPubMed Wouters BG, et al. Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital. Radiat Res. 2015;183(2):174–87.CrossRefPubMed
25.
go back to reference Paganetti H, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002;53(2):407–21.CrossRefPubMed Paganetti H, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002;53(2):407–21.CrossRefPubMed
26.
go back to reference Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: an update. Radiat Prot Dosim. 2015;166(1–4):334–8.CrossRef Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: an update. Radiat Prot Dosim. 2015;166(1–4):334–8.CrossRef
27.
go back to reference Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: what we know and don't know. Radiat Res. 2013;179(3):257–72.CrossRefPubMed Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: what we know and don't know. Radiat Res. 2013;179(3):257–72.CrossRefPubMed
29.
go back to reference Lühr A, et al. Does the RBE depend on ion type? Radiother Oncol. 2017;123(S1):123.CrossRef Lühr A, et al. Does the RBE depend on ion type? Radiother Oncol. 2017;123(S1):123.CrossRef
30.
go back to reference El Shafie RA, et al. In vitro evaluation of photon and raster-scanned carbon ion radiotherapy in combination with gemcitabine in pancreatic cancer cell lines. J Radiat Res. 2013;54(Suppl 1):i113–9.CrossRefPubMedPubMedCentral El Shafie RA, et al. In vitro evaluation of photon and raster-scanned carbon ion radiotherapy in combination with gemcitabine in pancreatic cancer cell lines. J Radiat Res. 2013;54(Suppl 1):i113–9.CrossRefPubMedPubMedCentral
31.
go back to reference Combs SE, et al. In vitro evaluation of photon and carbon ion radiotherapy in combination with chemotherapy in glioblastoma cells. Radiat Oncol. 2012;7:9.CrossRefPubMedPubMedCentral Combs SE, et al. In vitro evaluation of photon and carbon ion radiotherapy in combination with chemotherapy in glioblastoma cells. Radiat Oncol. 2012;7:9.CrossRefPubMedPubMedCentral
32.
go back to reference Naumann P, et al. Sulforaphane enhances irradiation effects in terms of perturbed cell cycle progression and increased DNA damage in pancreatic cancer cells. PLoS One. 2017;12(7):e0180940.CrossRefPubMedPubMedCentral Naumann P, et al. Sulforaphane enhances irradiation effects in terms of perturbed cell cycle progression and increased DNA damage in pancreatic cancer cells. PLoS One. 2017;12(7):e0180940.CrossRefPubMedPubMedCentral
33.
go back to reference Habermehl D, et al. The relative biological effectiveness for carbon and oxygen ion beams using the raster-scanning technique in hepatocellular carcinoma cell lines. PLoS One. 2014;9(12):e113591.CrossRefPubMedPubMedCentral Habermehl D, et al. The relative biological effectiveness for carbon and oxygen ion beams using the raster-scanning technique in hepatocellular carcinoma cell lines. PLoS One. 2014;9(12):e113591.CrossRefPubMedPubMedCentral
34.
go back to reference Goodhead DT. Mechanisms for the biological effectiveness of high-LET radiations. J Radiat Res. 1999;40(Suppl):1–13.CrossRefPubMed Goodhead DT. Mechanisms for the biological effectiveness of high-LET radiations. J Radiat Res. 1999;40(Suppl):1–13.CrossRefPubMed
35.
go back to reference Rorvik E, et al. A phenomenological biological dose model for proton therapy based on linear energy transfer spectra. Med Phys. 2017;44(6):2586–94.CrossRefPubMed Rorvik E, et al. A phenomenological biological dose model for proton therapy based on linear energy transfer spectra. Med Phys. 2017;44(6):2586–94.CrossRefPubMed
36.
go back to reference Weyrather WK, Kraft G. RBE of carbon ions: experimental data and the strategy of RBE calculation for treatment planning. Radiother Oncol. 2004;73(Suppl 2):S161–9.CrossRefPubMed Weyrather WK, Kraft G. RBE of carbon ions: experimental data and the strategy of RBE calculation for treatment planning. Radiother Oncol. 2004;73(Suppl 2):S161–9.CrossRefPubMed
37.
go back to reference Elsässer T, Krämer M, Scholz M. Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo. Int J Radiat Oncol Biol Phys. 2008;71(3):866–72.CrossRefPubMed Elsässer T, Krämer M, Scholz M. Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo. Int J Radiat Oncol Biol Phys. 2008;71(3):866–72.CrossRefPubMed
38.
go back to reference Friedland W, et al. Simulation of DNA damage after proton irradiation. Radiat Res. 2003;159(3):401–10.CrossRefPubMed Friedland W, et al. Simulation of DNA damage after proton irradiation. Radiat Res. 2003;159(3):401–10.CrossRefPubMed
39.
go back to reference Friedland W, et al. Simulation of DNA damage after proton and low LET irradiation. Radiat Prot Dosim. 2002;99(1–4):99–102.CrossRef Friedland W, et al. Simulation of DNA damage after proton and low LET irradiation. Radiat Prot Dosim. 2002;99(1–4):99–102.CrossRef
40.
go back to reference Friedland W, et al. Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. Mutat Res. 2011;711(1–2):28–40.CrossRefPubMed Friedland W, et al. Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. Mutat Res. 2011;711(1–2):28–40.CrossRefPubMed
41.
go back to reference Scholz M, Kraft G. Track structure and the calculation of biological effects of heavy charged particles. Adv Space Res. 1996;18:5.CrossRefPubMed Scholz M, Kraft G. Track structure and the calculation of biological effects of heavy charged particles. Adv Space Res. 1996;18:5.CrossRefPubMed
42.
go back to reference Elsässer T, Weyrather WK, Friedrich T. Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning. Int J Radiat Oncol Biol Phys. 2010;78:1177.CrossRefPubMed Elsässer T, Weyrather WK, Friedrich T. Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning. Int J Radiat Oncol Biol Phys. 2010;78:1177.CrossRefPubMed
43.
go back to reference Friedrich T, et al. Calculation of the biological effects of ion beams based on the microscopic spatial damage distribution pattern. Int J Radiat Biol. 2012;88(1–2):103–7.CrossRefPubMed Friedrich T, et al. Calculation of the biological effects of ion beams based on the microscopic spatial damage distribution pattern. Int J Radiat Biol. 2012;88(1–2):103–7.CrossRefPubMed
44.
go back to reference Schmid TE, et al. Sub-micrometer 20MeV protons or 45MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks. Mutat Res Genet Toxicol Environ Mutagen. 2015;793:30–40.CrossRefPubMed Schmid TE, et al. Sub-micrometer 20MeV protons or 45MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks. Mutat Res Genet Toxicol Environ Mutagen. 2015;793:30–40.CrossRefPubMed
45.
go back to reference Schmid TE, et al. Low LET protons focused to submicrometer shows enhanced radiobiological effectiveness. Phys Med Biol. 2012;57(19):5889–907.CrossRefPubMed Schmid TE, et al. Low LET protons focused to submicrometer shows enhanced radiobiological effectiveness. Phys Med Biol. 2012;57(19):5889–907.CrossRefPubMed
46.
go back to reference Kellerer AM, Lam YM, Rossi HH. Biophysical studies with spatially correlated ions. 4. Analysis of cell survival data for diatomic deuterium. Radiat Res. 1980;83(3):511–28.CrossRefPubMed Kellerer AM, Lam YM, Rossi HH. Biophysical studies with spatially correlated ions. 4. Analysis of cell survival data for diatomic deuterium. Radiat Res. 1980;83(3):511–28.CrossRefPubMed
47.
go back to reference Rossi HH. Biophysical studies with spatially correlated ions. 1. Background and theoretical considerations. Radiat Res. 1979;78(2):185–91.CrossRefPubMed Rossi HH. Biophysical studies with spatially correlated ions. 1. Background and theoretical considerations. Radiat Res. 1979;78(2):185–91.CrossRefPubMed
48.
go back to reference Ilicic K, Greubel C, Walsh D, Siebenwirth C, Girst S, Reindl J, Zlobinskaya O, Dollinger G, Multhoff G, Schmid TE. 20 MeV protons focused to sub-micrometer show enhanced radiobiological effectiveness in the clonogenic survival assay. In: 20th annual congress of the German Society for Radiation Oncology. Düsseldorf: Strahlentherapie und Onkologie; 2014. Ilicic K, Greubel C, Walsh D, Siebenwirth C, Girst S, Reindl J, Zlobinskaya O, Dollinger G, Multhoff G, Schmid TE. 20 MeV protons focused to sub-micrometer show enhanced radiobiological effectiveness in the clonogenic survival assay. In: 20th annual congress of the German Society for Radiation Oncology. Düsseldorf: Strahlentherapie und Onkologie; 2014.
50.
go back to reference Bettega D, et al. Radiobiological studies on the 65 MeV therapeutic proton beam at Nice using human tumour cells. Int J Radiat Biol. 2000;76(10):1297–303.CrossRefPubMed Bettega D, et al. Radiobiological studies on the 65 MeV therapeutic proton beam at Nice using human tumour cells. Int J Radiat Biol. 2000;76(10):1297–303.CrossRefPubMed
51.
go back to reference Petrovic I, et al. Response of a radioresistant human melanoma cell line along the proton spread-out Bragg peak. Int J Radiat Biol. 2010;86(9):742–51.CrossRefPubMed Petrovic I, et al. Response of a radioresistant human melanoma cell line along the proton spread-out Bragg peak. Int J Radiat Biol. 2010;86(9):742–51.CrossRefPubMed
52.
go back to reference Hojo H, et al. Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread out Bragg peak. Radiat Oncol. 2017;12(1):111.CrossRefPubMedPubMedCentral Hojo H, et al. Difference in the relative biological effectiveness and DNA damage repair processes in response to proton beam therapy according to the positions of the spread out Bragg peak. Radiat Oncol. 2017;12(1):111.CrossRefPubMedPubMedCentral
54.
go back to reference Slabbert J, et al. Increased proton relative biological effectiveness at the very end of a spread-out Bragg peak for jejunum irradiated ex vivo. Int J Part Ther. 2015;2:37–43.CrossRef Slabbert J, et al. Increased proton relative biological effectiveness at the very end of a spread-out Bragg peak for jejunum irradiated ex vivo. Int J Part Ther. 2015;2:37–43.CrossRef
55.
go back to reference Marshall TI, et al. Investigating the implications of a variable RBE on proton dose fractionation across a clinical pencil beam scanned spread-out Bragg peak. Int J Radiat Oncol Biol Phys. 2016;95(1):70–7.CrossRefPubMedPubMedCentral Marshall TI, et al. Investigating the implications of a variable RBE on proton dose fractionation across a clinical pencil beam scanned spread-out Bragg peak. Int J Radiat Oncol Biol Phys. 2016;95(1):70–7.CrossRefPubMedPubMedCentral
56.
go back to reference Chaudhary P, et al. Variations in the processing of DNA double-strand breaks along 60-MeV therapeutic proton beams. Int J Radiat Oncol Biol Phys. 2016;95(1):86–94.CrossRefPubMedPubMedCentral Chaudhary P, et al. Variations in the processing of DNA double-strand breaks along 60-MeV therapeutic proton beams. Int J Radiat Oncol Biol Phys. 2016;95(1):86–94.CrossRefPubMedPubMedCentral
57.
go back to reference Guan F, et al. Spatial mapping of the biologic effectiveness of scanned particle beams: towards biologically optimized particle therapy. Sci Rep. 2015;5:9850.CrossRefPubMedPubMedCentral Guan F, et al. Spatial mapping of the biologic effectiveness of scanned particle beams: towards biologically optimized particle therapy. Sci Rep. 2015;5:9850.CrossRefPubMedPubMedCentral
58.
go back to reference Grun R, et al. Systematics of relative biological effectiveness measurements for proton radiation along the spread out Bragg peak: experimental validation of the local effect model. Phys Med Biol. 2017;62(3):890–908.CrossRefPubMed Grun R, et al. Systematics of relative biological effectiveness measurements for proton radiation along the spread out Bragg peak: experimental validation of the local effect model. Phys Med Biol. 2017;62(3):890–908.CrossRefPubMed
59.
go back to reference Peeler CR, et al. Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma. Radiother Oncol. 2016;121(3):395–401.CrossRefPubMedPubMedCentral Peeler CR, et al. Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma. Radiother Oncol. 2016;121(3):395–401.CrossRefPubMedPubMedCentral
Metadata
Title
New insights in the relative radiobiological effectiveness of proton irradiation
Authors
K. Ilicic
S. E. Combs
T. E. Schmid
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2018
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-018-0954-9

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