Unanticipated late effects in neutron and heavy ion therapy, not attributable to overdose, imply a qualitative difference between low and high LET therapy. We identify that difference as ‘ion kill’, associated with the spectrum of z/β in the radiation field, whose measurement we label ‘ion-kill dosimetry’

Chambaudet, A.

Cucinotta, F. A.

Fromm, M.

Katz, Robert

English

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University of Nebraska - Lincoln 
DigitalCommons@University of Nebraska - Lincoln 
Robert Katz Publications Research Papers in Physics and Astronomy 
May 2000 
Ion-Kill Dosimetry 
Robert Katz 
University of Nebraska-Lincoln, rkatz2@unl.edu 
F. A. Cucinotta 
NASA Johnson Space Center, Houston, TX, francis.cucinotta@unlv.edu 
M. Fromm 
University of Franche-Comté, Besançon (France) 
A. Chambaudet 
University of Franche-Comté, Besançon (France) 
Follow this and additional works at: https://digitalcommons.unl.edu/physicskatz 
 Part of the Physics Commons 
Katz, Robert; Cucinotta, F. A.; Fromm, M.; and Chambaudet, A., "Ion-Kill Dosimetry" (2000). Robert Katz 
Publications. 59. 
https://digitalcommons.unl.edu/physicskatz/59 
This Article is brought to you for free and open access by the Research Papers in Physics and Astronomy at 
DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Robert Katz Publications by 
an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. 
164
R. Katz et al.: Ion-Kill Dosimetry
Ion-Kill Dosimetry
R. Katz1, F.A. Cucinotta2, M. Fromm3, A. Chambaudet3
1. University of Nebraska, Lincoln, NE 68588-0111 (USA)
2. NASA Johnson Space Center, Houston, TX 77058-3696 (USA)
3. University of Franche-Comté, Besançon (France)
Abstract
Unanticipated late effects in neutron and heavy ion therapy, not attributable to overdose, imply a qualitative difference between
low and high LET therapy. We identify that difference as ‘ion kill’, associated with the spectrum of  z/b in the radiation field,
whose measurement we label ‘ion-kill dosimetry’.
KEYWORDS: Ion-kill, biological dose, late effects, heavy ion therapy.
1. Late Effects in Heavy Ion Therapy
Neutron therapy in the UK has been accompanied
by unanticipated late effects, associated with loss of
repair, leading to the closing of all three installations
[1]. Such effects have also been observed at Berke-
ley with silicon and neon [2]. In discussing expe-
rience with He and Ne, Castro [3] mentioned that
tumor doses were expressed in physical Gray and
Gray equivalent. He stated that this was of some
value with protons or helium but was not as valid
or useful for heavier ions such as neon. Further,
fractionation did not protect against late effects for
neon as is the case for low-LET radiation. In all
cases treatment planning was based on ‘biological
dose’, the product of RBE and physical dose. Since
extensive and accurate measurements of RBE pre-
ceded treatment, the failure cannot be attributed to
overdose. We must conclude that biological dose is
an inadequate concept for high LET therapy, though
adequate for protons and helions. A quantitative
dosimetry which recognizes the qualitative differen-
ce between photons and heavy ions is required. We
propose that such a dosimetry can be based on track
theory.
2. A Precis of Track Theory
To explain the shapes of survival curves observed
with many different cell lines and different particle
beams we invoked a theory of dual radiation action,
the two modes being called ion-kill and gamma-kill.
Ion-kill is the effect produced by single energetic
heavy ions traversing a cell nucleus, while gamma-
kill is the effect produced by delta rays from adja-
cent ions on cells at most sub-lethally inactivated by
single ion traversals. In both cases the effects are
produced by delta rays, but the high concentration
of low energy delta rays close to an ion’s path is
a much more severe effect than that produced by the
dispersed delta rays from different ions in the gam-
ma-kill mode.
Gamma-kill physically resembles the inactivation
by the Compton- and photo-electrons from photon
irradiation. Ion–kill is responsible for all high-LET
effects: elevated RBE, reduced OER, loss of repair,
insensitivity to cell cycle differences.
In the theory the probability for ion-kill is used
as an approximation for the fraction of the dose
consumed in the ion-kill mode, with the residue
called the gamma-kill dose. Ion-kill effects are cal-
culated from the ion-kill cross section and the par-
ticle fluence, while gamma-kill effects are calcula-
ted from the same multi-target formula used for
calculating the survival curve for gamma-rays. Thus
the gamma-kill dose is fully equivalent to an equal
photon dose, as confirmed by our calculations of the
effects of radiation fields in which neutrons were
admixed with photons [4].
The theory requires the evaluation of four radiosen-
sitivity parameters from a collection of survival cur-
ves after exposure to particle beams of different com-
position and LET. Once evaluated these parameters
are used to calculate the response of arbitrary radia-
tion fields whose particle-energy spectrum is known
from calculation, for this measurement is presently
impossible. But the theory has shown that an arbi-
trary radiation field can be reduced to the total ion-
kill probability, and the total gamma-kill dose. The
ion-kill probability can be calculated from the distri-
bution in the spectrum of z/b in the radiation field and
the radiosensitivity parameters. From the theory a
measurement of total dose, and a measurement of the
ion-kill probability can yield calculations of cell sur-
vival, RBE and OER for those cells where in vitro
measurements have yielded radiosensitivity parame-
ters [5]. We anticipate that clinical experience will
identify the choice of radiosensitivity parameters
appropriate to different tissues and the levels of ion-
kill and dose correlated with unacceptable complica-
tions in high LET therapy.
1st International Workshop on Space Radiation Research and
11th Annual NASA Space Radiation Health Investigators’ Workshop
Arona (Italy), May 27-31, 2000
165
Physica Medica - Vol. XVII, Supplement 1, 2001
3. Calculations of Ion-Kill, RBE, and cell sur-
vival in a 2 cm spread Bragg Peak
To investigate the relation of ion-kill to these
problems we have calculated profiles of cell sur-
vival, physical dose, RBE, and probability for
survival in the ion-kill mode for beams of H, He,
C, and Ne, in a 2 cm spread Bragg peak, for which
there is 30% iso-survival [6]. This paper should be
consulted for further background, formulas and
illustrations for which there is no space here. The
regular decrease in ion-kill from neon through
carbon and helium to protons is consistent with
clinical observation of late effects, and has led us
to identify ion-kill as the source of this problem.
Although we have not yet calculated the distribution
of ion-kill probability as a function of depth in
neutron irradiated tissue, some of our earlier work
[7] yielded a calculation of the ion- kill probability
for neutrons of known initial energy for which the
fragment particle-energy distribution had been cal-
culated from experimental cross sections (Caswell
and Coyne and Dennis, pvt. communication). There
the ion kill probability increased regularly from
about 0.24 for 14 MeV neutrons to 0.65 for 0.5
MeV neutrons, for hamster cells, with small varia-
tion for other cell lines. The neutron energy spectrum
for the MRC installation at Hammersmith hospital
yielded a value of 0.2, while that from pion stars
was 0.15.
4. Ion Kill Dosimetry
Now, as to ion kill dosimetry. Clearly, we require
discriminating detectors, which respond preferen-
tially to single energetic heavy ions compared to
single electrons or protons, as is the case for
biological cells. Studies from track theory have
identified a number of such discriminating detectors
in physics and chemistry. Our preferred initial
selection is the class of solid state track etch
detectors where a heavy ion transit through the
detector creates a latent damage trail which is
exposed by chemical etching. In their application
to the measurement of the particle spectrum of
cosmic rays it has been useful to correlate ‘etching
rate’, the size of etch pits after specified etching
times, to z/b [8]. Different detectors span a range
of this quantity from 10 to 250 for relativistic
cosmic rays. They can be expected to be useful for
the evaluation of the biological effect of single
heavy ions in space. We will investigate their utility
for the spectrum of energetic heavy ions in cancer
therapy. Knowledge of the spectrum of z/b in tissue
may be converted to the spectrum of ion kill
probability by use of track theory. We anticipate
that this new information will aid radiation onco-
logists in their treatment planning, to avoid late
effects while yet taking advantage of the beneficial
effects of high LET radiation
REFERENCES
[1] Duncan W and Fowler JF. Particle Radiotherapy. Chapter
4.7.2. In: Oxford Textbook of Oncology, Second Edition.
Souhami RL, Tannock I, Hohenberger P, Horiot JC Eds.
Oxford University Press 2001 (in press).
[2] Blakely EA, Castro JR. Assessment of Acute and Late
Effects to High LET Radiation. Proceedings of NIRS
International Seminar on the Application of Heavy Ion
Accelerator to Radiation Therapy of Cancer, 21’st PTCOG
meeting, Chiba-Shi, 1994; 149-157.
[3] Castro JR. Results of Heavy Ion Therapy. Radiat Environ
Biophys 1995: 34; 435-448.
[4] Katz R. Sharma SC. Cellular Survival in a Mixed Ra-
diation Field. Int Jour Radiat Biol 1974: 26; 143-146.
[5] Katz R, Zachariah R, Zhang CX, Cucinotta FA. A Survey
of Cellular Radiosensitivity Parameters. Radiat Res 1994:
140; 356-365.
[6] Katz R, Cucinotta FA. Tracks to Therapy. Radiat Meas
1999: 31; 379-388.
[7] Katz R, Sharma SC. RBE-Dose Relations for Neutrons
and Pions. Phys Med Biol 1975: 20; 410-419.
[8] Ahlen SP, Coan TE, Drach J, Guo S-L, Price PB,
Salamon MH, Tarle G, Tincknell ML. Identification of
Relativistic Nuclei with 10 £ Z £ 92. Nuclear Tracks and
Radiat Meas 1984: 8; 571-572.


Ion-Kill Dosimetry

DigitalCommons@University of Nebraska

University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Robert Katz Publications Research Papers in Physics and Astronomy May 2000 Ion-Kill Dosimetry Robert Katz University of Nebraska-Lincoln, rkatz2@unl.edu F. A. Cucinotta NASA Johnson Space Center, Houston, TX, francis.cucinotta@unlv.edu M. Fromm University of Franche-Comté, Besançon (France) A. Chambaudet University of Franche-Comté, Besançon (France) Follow this and additional works at: https://digitalcommons.unl.edu/physicskatz  Part of the Physics Commons Katz, Robert; Cucinotta, F. A.; Fromm, M.; and Chambaudet, A., "Ion-Kill Dosimetry" (2000). Robert Katz Publications. 59. https://digitalcommons.unl.edu/physicskatz/59 This Article is brought to you for free and open access by the Research Papers in Physics and Astronomy at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Robert Katz Publications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. 164R. Katz et al.: Ion-Kill DosimetryIon-Kill DosimetryR. Katz1, F.A. Cucinotta2, M. Fromm3, A. Chambaudet31. University of Nebraska, Lincoln, NE 68588-0111 (USA)2. NASA Johnson Space Center, Houston, TX 77058-3696 (USA)3. University of Franche-Comté, Besançon (France)AbstractUnanticipated late effects in neutron and heavy ion therapy, not attributable to overdose, imply a qualitative difference betweenlow and high LET therapy. We identify that difference as ‘ion kill’, associated with the spectrum of  z/b in the radiation field,whose measurement we label ‘ion-kill dosimetry’.KEYWORDS: Ion-kill, biological dose, late effects, heavy ion therapy.1. Late Effects in Heavy Ion TherapyNeutron therapy in the UK has been accompaniedby unanticipated late effects, associated with loss ofrepair, leading to the closing of all three installations[1]. Such effects have also been observed at Berke-ley with silicon and neon [2]. In discussing expe-rience with He and Ne, Castro [3] mentioned thattumor doses were expressed in physical Gray andGray equivalent. He stated that this was of somevalue with protons or helium but was not as validor useful for heavier ions such as neon. Further,fractionation did not protect against late effects forneon as is the case for low-LET radiation. In allcases treatment planning was based on ‘biologicaldose’, the product of RBE and physical dose. Sinceextensive and accurate measurements of RBE pre-ceded treatment, the failure cannot be attributed tooverdose. We must conclude that biological dose isan inadequate concept for high LET therapy, thoughadequate for protons and helions. A quantitativedosimetry which recognizes the qualitative differen-ce between photons and heavy ions is required. Wepropose that such a dosimetry can be based on tracktheory.2. A Precis of Track TheoryTo explain the shapes of survival curves observedwith many different cell lines and different particlebeams we invoked a theory of dual radiation action,the two modes being called ion-kill and gamma-kill.Ion-kill is the effect produced by single energeticheavy ions traversing a cell nucleus, while gamma-kill is the effect produced by delta rays from adja-cent ions on cells at most sub-lethally inactivated bysingle ion traversals. In both cases the effects areproduced by delta rays, but the high concentrationof low energy delta rays close to an ion’s path isa much more severe effect than that produced by thedispersed delta rays from different ions in the gam-ma-kill mode.Gamma-kill physically resembles the inactivationby the Compton- and photo-electrons from photonirradiation. Ion–kill is responsible for all high-LETeffects: elevated RBE, reduced OER, loss of repair,insensitivity to cell cycle differences.In the theory the probability for ion-kill is usedas an approximation for the fraction of the doseconsumed in the ion-kill mode, with the residuecalled the gamma-kill dose. Ion-kill effects are cal-culated from the ion-kill cross section and the par-ticle fluence, while gamma-kill effects are calcula-ted from the same multi-target formula used forcalculating the survival curve for gamma-rays. Thusthe gamma-kill dose is fully equivalent to an equalphoton dose, as confirmed by our calculations of theeffects of radiation fields in which neutrons wereadmixed with photons [4].The theory requires the evaluation of four radiosen-sitivity parameters from a collection of survival cur-ves after exposure to particle beams of different com-position and LET. Once evaluated these parametersare used to calculate the response of arbitrary radia-tion fields whose particle-energy spectrum is knownfrom calculation, for this measurement is presentlyimpossible. But the theory has shown that an arbi-trary radiation field can be reduced to the total ion-kill probability, and the total gamma-kill dose. Theion-kill probability can be calculated from the distri-bution in the spectrum of z/b in the radiation field andthe radiosensitivity parameters. From the theory ameasurement of total dose, and a measurement of theion-kill probability can yield calculations of cell sur-vival, RBE and OER for those cells where in vitromeasurements have yielded radiosensitivity parame-ters [5]. We anticipate that clinical experience willidentify the choice of radiosensitivity parametersappropriate to different tissues and the levels of ion-kill and dose correlated with unacceptable complica-tions in high LET therapy.1st International Workshop on Space Radiation Research and11th Annual NASA Space Radiation Health Investigators’ WorkshopArona (Italy), May 27-31, 2000165Physica Medica - Vol. XVII, Supplement 1, 20013. Calculations of Ion-Kill, RBE, and cell sur-vival in a 2 cm spread Bragg PeakTo investigate the relation of ion-kill to theseproblems we have calculated profiles of cell sur-vival, physical dose, RBE, and probability forsurvival in the ion-kill mode for beams of H, He,C, and Ne, in a 2 cm spread Bragg peak, for whichthere is 30% iso-survival [6]. This paper should beconsulted for further background, formulas andillustrations for which there is no space here. Theregular decrease in ion-kill from neon throughcarbon and helium to protons is consistent withclinical observation of late effects, and has led usto identify ion-kill as the source of this problem.Although we have not yet calculated the distributionof ion-kill probability as a function of depth inneutron irradiated tissue, some of our earlier work[7] yielded a calculation of the ion- kill probabilityfor neutrons of known initial energy for which thefragment particle-energy distribution had been cal-culated from experimental cross sections (Caswelland Coyne and Dennis, pvt. communication). Therethe ion kill probability increased regularly fromabout 0.24 for 14 MeV neutrons to 0.65 for 0.5MeV neutrons, for hamster cells, with small varia-tion for other cell lines. The neutron energy spectrumfor the MRC installation at Hammersmith hospitalyielded a value of 0.2, while that from pion starswas 0.15.4. Ion Kill DosimetryNow, as to ion kill dosimetry. Clearly, we requirediscriminating detectors, which respond preferen-tially to single energetic heavy ions compared tosingle electrons or protons, as is the case forbiological cells. Studies from track theory haveidentified a number of such discriminating detectorsin physics and chemistry. Our preferred initialselection is the class of solid state track etchdetectors where a heavy ion transit through thedetector creates a latent damage trail which isexposed by chemical etching. In their applicationto the measurement of the particle spectrum ofcosmic rays it has been useful to correlate ‘etchingrate’, the size of etch pits after specified etchingtimes, to z/b [8]. Different detectors span a rangeof this quantity from 10 to 250 for relativisticcosmic rays. They can be expected to be useful forthe evaluation of the biological effect of singleheavy ions in space. We will investigate their utilityfor the spectrum of energetic heavy ions in cancertherapy. Knowledge of the spectrum of z/b in tissuemay be converted to the spectrum of ion killprobability by use of track theory. We anticipatethat this new information will aid radiation onco-logists in their treatment planning, to avoid lateeffects while yet taking advantage of the beneficialeffects of high LET radiationREFERENCES[1] Duncan W and Fowler JF. Particle Radiotherapy. Chapter4.7.2. In: Oxford Textbook of Oncology, Second Edition.Souhami RL, Tannock I, Hohenberger P, Horiot JC Eds.Oxford University Press 2001 (in press).[2] Blakely EA, Castro JR. Assessment of Acute and LateEffects to High LET Radiation. Proceedings of NIRSInternational Seminar on the Application of Heavy IonAccelerator to Radiation Therapy of Cancer, 21’st PTCOGmeeting, Chiba-Shi, 1994; 149-157.[3] Castro JR. Results of Heavy Ion Therapy. Radiat EnvironBiophys 1995: 34; 435-448.[4] Katz R. Sharma SC. Cellular Survival in a Mixed Ra-diation Field. Int Jour Radiat Biol 1974: 26; 143-146.[5] Katz R, Zachariah R, Zhang CX, Cucinotta FA. A Surveyof Cellular Radiosensitivity Parameters. Radiat Res 1994:140; 356-365.[6] Katz R, Cucinotta FA. Tracks to Therapy. Radiat Meas1999: 31; 379-388.[7] Katz R, Sharma SC. RBE-Dose Relations for Neutronsand Pions. Phys Med Biol 1975: 20; 410-419.[8] Ahlen SP, Coan TE, Drach J, Guo S-L, Price PB,Salamon MH, Tarle G, Tincknell ML. Identification ofRelativistic Nuclei with 10 £ Z £ 92. Nuclear Tracks andRadiat Meas 1984: 8; 571-572.

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