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Radiation absorbed dose estimates at the cellular level for some electron-emitting radionuclides for radioimmunotherapy
hr. 1. A@. Rodiar. Isol. Vol. 35. No. 9. pp. 883-888, Printed in Great Britain
1984
0020-708X:81 53.00 + 0.00 Pergamoa Press Ltd
Radiation Absorbed Dose Estimates at the Cellular Level for Some Electron-Emitting Radionuclides for Radioimmunotherapy JOHN A. JUNGERMAN,
KIN-HUNG
P. YU* and CLAUDIO
I. ZANELLI
Physics Department, University of California, Davis, CA 95616, U.S.A. (Received 22 June 1983; in revised form 30 November 1983)
Calculation of the radiation dose at the cellular level is given for several radionuclides that appear promising for radioimmunotherapy using the radiation dose distribution from a point source. The radionuclides have half-lives in the 1-3 day range and have electron ranges up to several hundred micrometers. The investigation emphasizes the physical considerations in radionuclide choice for the radiolabeling of monoclonal antibodies or antibody fragments.
1. Introduction The use of monoclonal antibodies or antibody fragments with a suitable radiolabel offers the attractive possibility of administering a radiation absorbed dose to tumor cells with a minimum of radiation to surrounding benign tissue. This is to be contrasted with x- or y-radiation therapy wherein the radiation energy is delivered externally and hence passes through benign tissue both on entry and exit from the tumor irradiation area. Below we discuss the physical considerations in radionuclide choice for the label and give calculations of the absorbed dose delivered at the cellular level. 2. Criteria for Choice of a Radionuclide Although there will undoubtedly be additional biological and chemical criteria for selection of a radionuclide, the discussion here concerns the optimization of the microdosimetry. At present, the ,time required for the labelled antibody to find its tumor antigen and to deliver its dose in the tumor is estimated to be of the order of 1-3 days.“’ We have therefore used the criterion of a l-3 day half-life in choosing a radionuclide. A longer half-life would lead to increased nontarget patient dose if the antibodies are shed before the radioactive decay. Given the time limitation imposed by shedding, it is advantageous to restrict half lives to closely match the residence time, which will depend on tumor, antibody and physiological factors.
l
1982 Summer Fellow Associated Westem Universities. 883
It is also not known at present whether or not there will be effective deposition of the radiolabelled antibody on all tumor cells even though many antigen sites are available on each cell, due to poor blood supply to the tumor cell for example. In this case a variety of electron ranges up to approximately 300 pm or about 30 cell diameters, appears useful for initial radioimmunotherapy investigations. If the radiolabel reaches almost all tumor cells, then it is desirable to have a radionuclide with an electron range which at a minimum is snfllcient to reach the nucleus of a mammalian cell from the periphery where the antigen sites are located (typically 5 pm). We also require that the daughter nucleus be stable or very nearly so in order to avoid additional dose to other tissues in the patient. For the same reason 7 rays and high-energy x rays should also be minimized unless they are expressly needed for diagnosticimaging purposes. A final practical criterion has been that the radionuclide can readily be produced by a medium-energy cyclotron or similar accelerator. We report below microdosimetric calculations for seven electron-emitting radionuclides possessing a variety of electron ranges that meet the above criteria. Also included for comparison purposes is 13’1,which has been used previousiy in radioimmunotherapy.o’
3. Microdosimetry
Calculations
The radionuclides selected for preliminary investigation and microdosimetric calculation are 67Cu, 97R~, ““‘Pd, ‘“‘mRh ‘19Sb. l”I, “‘I, and 19’Hg. 67Cu, 97R~, ‘O”Pd,and ‘O”Rh, l”I and possibly 19’Hg can also be imaged, and have a variety of possibly
JOHN A. JUNGLRMAN et al.
884
Table 1. Emissions from several radionuclides of therapeutic interest. (& refers to the energy of phorons and conversion electrons and the average energy of g-ray emitters) Nuclide 6’Cu(r,,2 = 2.58 days) p-ray 577 keV (E_) g-ray 484 keV (E_) g-ray 395 keV (g,) 7 -my Y-my ‘/-my 7 -ray
9TR~(r,,, = 2.88 days) L-Auger/electron K-Auger/electron K-Auger/electron c0nv. eL-x-ray K-x-ray 7 -ray y-ray ‘O”Pd(r,,,= 3.64 days) L*Auger/electron K-Auger/electron K-Auger/electron K-Auger/electron L-cow e- (a) L-cow e- (b) K-conv e- (a) Ktonv e- (b) L-x-ray K-x-ray 7-ray y-ray (a) y-ray (b) 7-ray (c) ?-ray (d) “9Sb(r,,r = 1.58 days) L-Auger-electron L-cow eK-Auger-electron K-x-ray T-ray ‘sl”Rh(r,,, = 4.34 days) L-Auger-electron K-Auger-electron K-Auger-electron K-Auger-electron L-x-ray K-x-ray 7 -ray 7-raY ‘“I@,, = 0.55 days) L-Auger-electron K-Auger-electron K-cow eL-x-ray K-x-ray 7 -ray “‘I(r,,, = 8.04 days) I% 807 keV, Ema,. -10 g-ray fiO6keV. &,,,. 86% 336 keV, E_. 13% 7-t-aY y-ray r-my ?-ray ‘P’Hg(r,,, = 2.71 days)** L-Auger-electron K-Auger-electron L-cow eM-conv eL-x-ray K-x-ray y-ray
$(keV)
Intensity,‘decay
192.3 161.3 131.7 91.3 93.3 184.5 300.2
16.9% 47% 0.7%
2.2 15.5 17.8 193.6 2.6 19.28 215.7 324.5
95.7% 15.8% 5.5% 3.0% 8.3% 77.9% 86% 10.3%
2.2 16.8 19.5 22.2 71.4 80.6 51.6 60.8 2.70 21.2 33 74.8
91% 13.6% 4.5% 0.8% 2.0% 4.4% 16.5% 30.9% 9% 81%
20% 35% 45%
,7.3%
x&m) 762 562 461
0.18 3.8 5.5 374
0.185 4.5 4.46 7.5 58.6 36.5 43.3 0.42
126.1 158.8
39.z 57.1p; 10.3% 1.8%
4.0 19.1 21.0 26.4 23.8
88% 86.3% 14.1% 85.9% 13.7%
0.42 6.2 7.0
2.2 16.4 18.8 21.2 2.7 2012 306.8 545
91.7% 13.6% 4.7% 0.8% 8.4% 73.6% 87% 4.0%
0.19 4.1 6.9 7.0
95%
0.29 7.52 151
84.0
3.2 22.7 127.2 3.8 28.6 159.0
1I .8% 11.3% 88.? 82.92
183
100%
80. I 284.3 364.5 637.0
2.6% 6.0% 81% 7.2%
I2 52 63.6 74. I II 70.8 77.4
58% 3.6% 64.9% 14.9% 30% 96.4% 19.00/,
022
2.5 33 48 62
**Data provided by Dr E. Browne.“” M conversion electrons were not included in the absorbed dose rate calculation.
Radiation absorbed dose estimates of electron emitters useful electron ranges. “‘Sb on the other hand has very little photon radiation. The frequency of conversion electron and photon radiation for each radionuclide was determined from the decay schemes of Lederer and Shirley.O) K- and L-Auger electron intensities and energies were determined from the article of Bergstrom and Nordling.(4) No attempt was made in the present calculation to separate the various Auger subshells, but an average value of K- and L-electron energies was used as well as the total estimated intensities. For the b-ray emitters “‘I and ‘j’Cu the conversion electron contribution was not included since it is small. Table 1 gives the principal photon and electron emissions for the radionuclides considered and which were included in the calculation. We have used the compilation of Berger,‘s) which is based on electron multiple-scattering calculations of Spencer@) for a point isotropic source to determine absorbed dose to tissue from the electrons. All calculations are performed for water to simulate a tumor environment. According to the MIRD notation,‘” the absorbed dose rate is expressed as
where R(x,E,) is the amount of energy per unit mass per unit time deposited at a distance x from a source of energy E,,, in rad/s.* (see footnote), A is the source activity, in number of disintegrations/St, n is the mean number of electrons of energy E. emitted per disintegration, k = 1.6 x lo-‘g*rad/MeV, E. is the initial energy of the emitted electrons in MeV, 4(x,&) is the fraction of the emitted energy that is absorbed at distance x per unit mass of the medium (also called specific absorbed fraction). Using the dimensionless quantity x/xw, (i.e. the ratio of the distance to the source to the distance at which 90% of the energy is deposited) Ref. (5) provides means of computing 9(x, E,,) by publishing the scaled absorbed dose distribution, F(x/x,.E,) defined as
which is very nearly independent of the medium (of density 6). Since the values of F(x/x,,E,,) are given only for discrete values of x/x% and E,, careful interpolation was required in our computation of 4&G). In the case of p-ray emitters the situation is somewhat more complex, as it requires integration over the b-ray spectrum S(E): RB(x)=An&
Emu EoWo)
s0
9 (xv & Wo
* The SI named unit for absorbed rate, gray per second (Gys-‘) is qua1 to IOOrads-‘. t The SI name unit for activity, becquerel (Bq) iS equal to I disintegration/s, the older unit curie (Ci) equals exactly 3.7 x 10’0Bq.
885
and the specific absorbed fraction for a given @-ray source becomes I-E,..
4a(~) =
1 “_^ (EoI&v)Wo) d(x,Eo)dEo
JO
EAV=
EoWo Wo
If the p-ray spectrum has more than one component they must be added to arrive at the final values of #a(x) and R,(x). For photon radiation (9 and x-rays), the specific absorbed fraction is simply
where l/r is the distance at which a photon beam is attenuated to l/e. A complete dose-rate calculation involves adding the contributions from monoenergetic electrons, B-ray electrons, and photons, which can be summarized as R(x) = AK C +%i(x,Ei) ephotons
+ C Q’~v,+~j(X) br -I
In the case of Auger and conversion electrons we used the scaled absorbed dose distribution F(x/x,, E. ) of Berger”) for monoenergetic electrons in conjunction with the percentile-distance ratio, x/x%, in water for monoenergetic sources given in the same reference. For each radionuclide the distribution of dose rate as a function of distance from the source was calculated for each electron group, and the results were summed to give the total contribution of electrons to absorbed dose rate. These calculations were carried out to 1 cm, which is about 1000 mammalian-cell diameters and therefore larger than the electron ranges of the radionuclides investigated. The photon contribution to radiation absorbed dose rate was also calculated as a function of distance from the source for the x-ray and ‘/-ray contributions given in Table 1. For this purpose we used the total attenuation coefficient for photons in water as given by Evans. (‘) ‘They were then added to the electron radial radiation dose distribution to give the total dose rate R(x) at a given distance x from a point source for a given radionuclide. The total photon contribution to dose rate is at most only a few percent of the total electron absorbed dose for the distances from the source considered here. The resulting quantity, R/A, in rad s-i PCi-’ is plotted in Figs 1 and 2 as a function of x. Since the I/r* behavior masks to some extent the differences among the radionuclides as to the absorbed dose rate as a function of distance from the source, the quantity 4nx*RIA was also calculated. This quantity, when multiplied by the density p,
JOHN A. JIJNGERMAN et al.
886
L.
103
..
103t1, \ -\
lo105
G > \”
-
105
-
lo4
-
103IO2 -
0 El0
1
-
10-l lo-'-
IO‘310-Z
lo-4-
10“
1
10-2
10
102
IO'
104
pm
10-~ lo-!
1
10
IO2
IO3
lo4
Pm
Fig. 1. Radiation absorbed dose rate in rad S-I per pCi as a function of distance from a point source for Wu, 97Ru, IwPd, and IOlmRh.(The data for “Cu are approximate only.)
Fig. 3. Differential energy absorption rate per unit mass thickness (in units of absorbed dose rate unity activity x area) spherical shell of radius x (41rx2R/A ) from a point source of *‘Cu, 97R~, ‘O”Pd,and ““‘WI.
is
becomes the amount of energy deposited per unit thickness in a spherical shell of radius r per unit time per unit activity and nullifies the l/r’ dependence. Figures 3 and 4 give the results of this calculation. From these figures it can be seen that “‘I and 67Cu are relatively long range /I-ray emitters, several hundred micrometers, whereas ‘19Sb,for example, has its major radiation dose contribution in less than 10 pm or approximately one mammalian-cell diameter. To provide a more quantitative measure of the range characteristics of each radionuclide, the integrals over r of the curves in Figs 3 and 4 were also calculated. This quantity, X rlrrr$dr, s0 log
J
IO' i
lo-’ 10-3
I
10-4 lo-'
-_-__ 731,
--______
r91np
\
-*.\,
1,
‘\
\ ‘\.:I, ‘%.
J
10-2
IO-'
1
10
IO2
IO3
104
Fig. 4. Differential energy absorption rate per unit mass thickness (in units of absorbed dose rate per unit activity x area) spherical shell of radius x (4nx2R/A) from a point source of “‘Sb, ‘% “‘1, and 19’Hg.
Radiation absorbed dose estimates of electron emitters
887
--._-._-.‘00p~
i 10-Z
1
Y____j I
....,I
10-l
10
102
10'
10-l
10-2
104
I I
10
102
103
jo4
w
Fig. 6. Integral energy absorption rate in a unit density sphere of radius x (in units of dose rate per unit
Fig. 5. Integral energy absorption rate in a unit density sphere of radius x (in units of dose rate per unit activity x sphere volume), up to radius x
activity x sphere volume), up to radius x
from a point source of ‘19Sb, IrJI, “‘I, and IP7Hg.
from a point source of 6’Cu9“Ru 1 ‘qd 9 and IoimRh. for all isotopes, and thus it was defined as the 100% distance. We fee.1that in this way a similarity to the percentile distance definition is preserved, while including the short-range photon contribution. As a summary for comparison purposes, Table 2 shows the values of xlo, xl5 and x,, accompanied with the dose rates per unit activity (in rad.s-‘.pCi-‘) at these distances. It is clear that ‘19Sb delivers most of its energy within subcellular distances, and accordingly, is not suitable for therapeutic processes that do not allow the radioactive substance to penetrate the cell-such as radioimmunotherapy(‘3)-for cells of diameters in the order of 10 pm. Table 2 also indicates that 19’Hg and ‘“Pd are nearly equivalent in range, by depositing 90% of the available energy in about 6 cell diameters. The difference between these two lies in the dose rates, which are -3 to 4 times larger for 19’Hg than for ‘O”Pdat x,. This indicates that for therapy, 19’Hg would be preferable unless the higher energy y rays of ““‘Pd are needed for monitoring purposes (see Table 1). lz31 can be considered a medium-range source, whereas 67Cu, 97R~ and “lmRh are of the longer range, sparsely-distributed dose type. Although 67Cu and 97R~ have somewhat similar percentile distances, the dose rate from 67Cu is 20 times larger than that
of 97Ru at 600 pm (w 60 cell diameters). Radiation confinement requirements, as well as production facilities and radiobiological factors must be taken into consideration in choosing among these two. ‘OlmRhhas mixed characteristics of short and long range radiation. It deposits 50% of its energy within 5 pm (which may not have radiotoxic effect)(‘” while its 90% distance is about 77 cell diameters (although the absorbed dose rate is quite low at x+,). A direct comparison between “‘I and 67Cu in Table 2 reveals their similarity, which can also be seen in Figs 1 and 2. The chief differences are in their half-lives and y-ray content, which make ‘j’Cu preferable for radioimmunotherapy. The radionuclides discussed above are already available from nuclear reactors (13’1) or spallation reactions C’Cu), or can be produced in a mediumenergy cyclotron. The nuclear reactions proposed for their production are given in Table 3. For each radionuclide a radiochemical labeling procedure is envisaged@’ but will not be discussed here. The present calculations were obtained via a computer program which calculates the quantity R/A and 4rcx*R/A and its radial integral directly from the energy-dissipation distributions of Spencer.(@ Input data for any radionuclide are the conversion- and Auger-electron spectra or /?-ray spectra, and the
Table 2. The distances (x) in micromeren for Wo/ 75%. and WA of the energy 10 be deposited up 10 I mmfrom a point source are lismd for the radioauclides studied. Ah shown are the values of absorbed dose rate in tads-’ pCi_’ at the respective distances. ‘OLafi Ul* q “cu 9’RU ‘qd ‘%b lnHg h Olm) ~~3 (pm) xw (/cm) R:A(xSO) R/A(x75) RIA(x90)
180 370 571 0.365 0.055 0.012
120 271 613 0.054 0.015 0.0004
25.6 38.3 57.4 52.2 22.3 2.26
4.80 422 767 -1156 0.001 0.0003
3.55 5.12 6.47 11720 6530 2420
82.7 131 249 0.558 0.282 0.006
263 493 713 0.165 0.030 0.009
31.1 43.3 55.1 52.9 28.9 9.54
JOHN A. JUNGERMAN et al.
888
Proc. Int. Symp. Shorter-Lived
Table 3. Production methods WJ P,RuW
Spallation
l-d”‘% lOl~~“O,
‘:$Wp.W’$F’d ,J’d(p.xn)‘:;Ag + ‘pd + ‘“:“;Rb
“‘Sb 12q,ll,
‘~~Sqp,3n)‘gre - ‘:$b. r)‘“&(p,50)‘~~e “‘l(p,Sn)‘~Xc + ‘“I
“II
Fission product
‘P’Hg
‘9*u(p.nYqg$-ig
‘O*RII(~,~TII)~RU
+ ‘$Sb
photon contribution. The availability of such a program, which produces absorbed dose data almost directly from a decay scheme, should facilitate future decisions concerning radionuclide choice that may arise because of new chemical, biological or medical information. Mcnowledgemenrs-It is a pleasure to acknowledge helpful conversations with Drs G. L. JlkNardo. S. J. DeNardo, H. H. Hines and M. C. Lagunas-Solar. Support from DOE Grant DE AT03-82 (S. J. DeNardo, principal investigator) is also gratefully acknowledged.
References I. DeNardo S. J., Jungerman J. A., DeNardo G. L., Lagunas-Solar
M. C., Cole W. C. and Meares C. F.
Radionuclides, Washinaton. D.C.. Mav 1982. DOE Conf. 820523 ORNL 19ii3. In press. ’ 2. Bale W. F., Spar J. S. and Goodland R. L. Cancer Res. 65, 779-793 (1960). 3. Lederer C. M. and Shirley V. S. (Eds) Table of Isotopes. (John Wiley, New York, 1978). 4. Bergstrom I. and Nordling C. In Afpha, Beta, and Gamma-Ray Spectroscopy. Siegbahn K. (Ed.) Vol. 2, pp. 1523-1543 (North Holland, Amsterdam, 1965). 5. Berger M. J. Nat. Bur. Stand. Report NBSIR 73-107, Feb. (1973). 6. Spencer L. V. Nat. Bur. Stand. Monogr. No. 1 (1959). 7. Evans R. D. The Atomic Nucleus. p. 714 (McGraw-Hill, 1955). 8. Lagunas-Solar M. C. Cracker Nuclear Laboratory, University of California, Davis, CA. Private communication. 9. Lagunas-Solar M. C.. Avila M. J., Navarro N. J. and Johnson P. C. Jnr. J. Appl. Radiat. Jsot. 35. 743 (1984). IO. Lagunas-Solar M. C.. Wilkins S. R. and Paulson‘D. W. J. Radioanal. Chem. 68. 245 I 19821.
Il. Wilkins S. R., ShimoseS. T.,‘Hines H. H., Jungerman J. A., Hegedus F. and DeNardo G. L. Int. J. Appl. Radiat. Isot. 26, 279 (1975). 12. Browne E. Lawrence Berkeley Laboratory,
University of California, Berkeley, CA. Private communication. 13. Kassis A. I., Adelstein S. J.. Haydock C. and Sastry S. R. J. Nucl. :Med. 24, 1164-1175 (1983).
1984
0020-708X:81 53.00 + 0.00 Pergamoa Press Ltd
Radiation Absorbed Dose Estimates at the Cellular Level for Some Electron-Emitting Radionuclides for Radioimmunotherapy JOHN A. JUNGERMAN,
KIN-HUNG
P. YU* and CLAUDIO
I. ZANELLI
Physics Department, University of California, Davis, CA 95616, U.S.A. (Received 22 June 1983; in revised form 30 November 1983)
Calculation of the radiation dose at the cellular level is given for several radionuclides that appear promising for radioimmunotherapy using the radiation dose distribution from a point source. The radionuclides have half-lives in the 1-3 day range and have electron ranges up to several hundred micrometers. The investigation emphasizes the physical considerations in radionuclide choice for the radiolabeling of monoclonal antibodies or antibody fragments.
1. Introduction The use of monoclonal antibodies or antibody fragments with a suitable radiolabel offers the attractive possibility of administering a radiation absorbed dose to tumor cells with a minimum of radiation to surrounding benign tissue. This is to be contrasted with x- or y-radiation therapy wherein the radiation energy is delivered externally and hence passes through benign tissue both on entry and exit from the tumor irradiation area. Below we discuss the physical considerations in radionuclide choice for the label and give calculations of the absorbed dose delivered at the cellular level. 2. Criteria for Choice of a Radionuclide Although there will undoubtedly be additional biological and chemical criteria for selection of a radionuclide, the discussion here concerns the optimization of the microdosimetry. At present, the ,time required for the labelled antibody to find its tumor antigen and to deliver its dose in the tumor is estimated to be of the order of 1-3 days.“’ We have therefore used the criterion of a l-3 day half-life in choosing a radionuclide. A longer half-life would lead to increased nontarget patient dose if the antibodies are shed before the radioactive decay. Given the time limitation imposed by shedding, it is advantageous to restrict half lives to closely match the residence time, which will depend on tumor, antibody and physiological factors.
l
1982 Summer Fellow Associated Westem Universities. 883
It is also not known at present whether or not there will be effective deposition of the radiolabelled antibody on all tumor cells even though many antigen sites are available on each cell, due to poor blood supply to the tumor cell for example. In this case a variety of electron ranges up to approximately 300 pm or about 30 cell diameters, appears useful for initial radioimmunotherapy investigations. If the radiolabel reaches almost all tumor cells, then it is desirable to have a radionuclide with an electron range which at a minimum is snfllcient to reach the nucleus of a mammalian cell from the periphery where the antigen sites are located (typically 5 pm). We also require that the daughter nucleus be stable or very nearly so in order to avoid additional dose to other tissues in the patient. For the same reason 7 rays and high-energy x rays should also be minimized unless they are expressly needed for diagnosticimaging purposes. A final practical criterion has been that the radionuclide can readily be produced by a medium-energy cyclotron or similar accelerator. We report below microdosimetric calculations for seven electron-emitting radionuclides possessing a variety of electron ranges that meet the above criteria. Also included for comparison purposes is 13’1,which has been used previousiy in radioimmunotherapy.o’
3. Microdosimetry
Calculations
The radionuclides selected for preliminary investigation and microdosimetric calculation are 67Cu, 97R~, ““‘Pd, ‘“‘mRh ‘19Sb. l”I, “‘I, and 19’Hg. 67Cu, 97R~, ‘O”Pd,and ‘O”Rh, l”I and possibly 19’Hg can also be imaged, and have a variety of possibly
JOHN A. JUNGLRMAN et al.
884
Table 1. Emissions from several radionuclides of therapeutic interest. (& refers to the energy of phorons and conversion electrons and the average energy of g-ray emitters) Nuclide 6’Cu(r,,2 = 2.58 days) p-ray 577 keV (E_) g-ray 484 keV (E_) g-ray 395 keV (g,) 7 -my Y-my ‘/-my 7 -ray
9TR~(r,,, = 2.88 days) L-Auger/electron K-Auger/electron K-Auger/electron c0nv. eL-x-ray K-x-ray 7 -ray y-ray ‘O”Pd(r,,,= 3.64 days) L*Auger/electron K-Auger/electron K-Auger/electron K-Auger/electron L-cow e- (a) L-cow e- (b) K-conv e- (a) Ktonv e- (b) L-x-ray K-x-ray 7-ray y-ray (a) y-ray (b) 7-ray (c) ?-ray (d) “9Sb(r,,r = 1.58 days) L-Auger-electron L-cow eK-Auger-electron K-x-ray T-ray ‘sl”Rh(r,,, = 4.34 days) L-Auger-electron K-Auger-electron K-Auger-electron K-Auger-electron L-x-ray K-x-ray 7 -ray 7-raY ‘“I@,, = 0.55 days) L-Auger-electron K-Auger-electron K-cow eL-x-ray K-x-ray 7 -ray “‘I(r,,, = 8.04 days) I% 807 keV, Ema,. -10 g-ray fiO6keV. &,,,. 86% 336 keV, E_. 13% 7-t-aY y-ray r-my ?-ray ‘P’Hg(r,,, = 2.71 days)** L-Auger-electron K-Auger-electron L-cow eM-conv eL-x-ray K-x-ray y-ray
$(keV)
Intensity,‘decay
192.3 161.3 131.7 91.3 93.3 184.5 300.2
16.9% 47% 0.7%
2.2 15.5 17.8 193.6 2.6 19.28 215.7 324.5
95.7% 15.8% 5.5% 3.0% 8.3% 77.9% 86% 10.3%
2.2 16.8 19.5 22.2 71.4 80.6 51.6 60.8 2.70 21.2 33 74.8
91% 13.6% 4.5% 0.8% 2.0% 4.4% 16.5% 30.9% 9% 81%
20% 35% 45%
,7.3%
x&m) 762 562 461
0.18 3.8 5.5 374
0.185 4.5 4.46 7.5 58.6 36.5 43.3 0.42
126.1 158.8
39.z 57.1p; 10.3% 1.8%
4.0 19.1 21.0 26.4 23.8
88% 86.3% 14.1% 85.9% 13.7%
0.42 6.2 7.0
2.2 16.4 18.8 21.2 2.7 2012 306.8 545
91.7% 13.6% 4.7% 0.8% 8.4% 73.6% 87% 4.0%
0.19 4.1 6.9 7.0
95%
0.29 7.52 151
84.0
3.2 22.7 127.2 3.8 28.6 159.0
1I .8% 11.3% 88.? 82.92
183
100%
80. I 284.3 364.5 637.0
2.6% 6.0% 81% 7.2%
I2 52 63.6 74. I II 70.8 77.4
58% 3.6% 64.9% 14.9% 30% 96.4% 19.00/,
022
2.5 33 48 62
**Data provided by Dr E. Browne.“” M conversion electrons were not included in the absorbed dose rate calculation.
Radiation absorbed dose estimates of electron emitters useful electron ranges. “‘Sb on the other hand has very little photon radiation. The frequency of conversion electron and photon radiation for each radionuclide was determined from the decay schemes of Lederer and Shirley.O) K- and L-Auger electron intensities and energies were determined from the article of Bergstrom and Nordling.(4) No attempt was made in the present calculation to separate the various Auger subshells, but an average value of K- and L-electron energies was used as well as the total estimated intensities. For the b-ray emitters “‘I and ‘j’Cu the conversion electron contribution was not included since it is small. Table 1 gives the principal photon and electron emissions for the radionuclides considered and which were included in the calculation. We have used the compilation of Berger,‘s) which is based on electron multiple-scattering calculations of Spencer@) for a point isotropic source to determine absorbed dose to tissue from the electrons. All calculations are performed for water to simulate a tumor environment. According to the MIRD notation,‘” the absorbed dose rate is expressed as
where R(x,E,) is the amount of energy per unit mass per unit time deposited at a distance x from a source of energy E,,, in rad/s.* (see footnote), A is the source activity, in number of disintegrations/St, n is the mean number of electrons of energy E. emitted per disintegration, k = 1.6 x lo-‘g*rad/MeV, E. is the initial energy of the emitted electrons in MeV, 4(x,&) is the fraction of the emitted energy that is absorbed at distance x per unit mass of the medium (also called specific absorbed fraction). Using the dimensionless quantity x/xw, (i.e. the ratio of the distance to the source to the distance at which 90% of the energy is deposited) Ref. (5) provides means of computing 9(x, E,,) by publishing the scaled absorbed dose distribution, F(x/x,.E,) defined as
which is very nearly independent of the medium (of density 6). Since the values of F(x/x,,E,,) are given only for discrete values of x/x% and E,, careful interpolation was required in our computation of 4&G). In the case of p-ray emitters the situation is somewhat more complex, as it requires integration over the b-ray spectrum S(E): RB(x)=An&
Emu EoWo)
s0
9 (xv & Wo
* The SI named unit for absorbed rate, gray per second (Gys-‘) is qua1 to IOOrads-‘. t The SI name unit for activity, becquerel (Bq) iS equal to I disintegration/s, the older unit curie (Ci) equals exactly 3.7 x 10’0Bq.
885
and the specific absorbed fraction for a given @-ray source becomes I-E,..
4a(~) =
1 “_^ (EoI&v)Wo) d(x,Eo)dEo
JO
EAV=
EoWo Wo
If the p-ray spectrum has more than one component they must be added to arrive at the final values of #a(x) and R,(x). For photon radiation (9 and x-rays), the specific absorbed fraction is simply
where l/r is the distance at which a photon beam is attenuated to l/e. A complete dose-rate calculation involves adding the contributions from monoenergetic electrons, B-ray electrons, and photons, which can be summarized as R(x) = AK C +%i(x,Ei) ephotons
+ C Q’~v,+~j(X) br -I
In the case of Auger and conversion electrons we used the scaled absorbed dose distribution F(x/x,, E. ) of Berger”) for monoenergetic electrons in conjunction with the percentile-distance ratio, x/x%, in water for monoenergetic sources given in the same reference. For each radionuclide the distribution of dose rate as a function of distance from the source was calculated for each electron group, and the results were summed to give the total contribution of electrons to absorbed dose rate. These calculations were carried out to 1 cm, which is about 1000 mammalian-cell diameters and therefore larger than the electron ranges of the radionuclides investigated. The photon contribution to radiation absorbed dose rate was also calculated as a function of distance from the source for the x-ray and ‘/-ray contributions given in Table 1. For this purpose we used the total attenuation coefficient for photons in water as given by Evans. (‘) ‘They were then added to the electron radial radiation dose distribution to give the total dose rate R(x) at a given distance x from a point source for a given radionuclide. The total photon contribution to dose rate is at most only a few percent of the total electron absorbed dose for the distances from the source considered here. The resulting quantity, R/A, in rad s-i PCi-’ is plotted in Figs 1 and 2 as a function of x. Since the I/r* behavior masks to some extent the differences among the radionuclides as to the absorbed dose rate as a function of distance from the source, the quantity 4nx*RIA was also calculated. This quantity, when multiplied by the density p,
JOHN A. JIJNGERMAN et al.
886
L.
103
..
103t1, \ -\
lo105
G > \”
-
105
-
lo4
-
103IO2 -
0 El0
1
-
10-l lo-'-
IO‘310-Z
lo-4-
10“
1
10-2
10
102
IO'
104
pm
10-~ lo-!
1
10
IO2
IO3
lo4
Pm
Fig. 1. Radiation absorbed dose rate in rad S-I per pCi as a function of distance from a point source for Wu, 97Ru, IwPd, and IOlmRh.(The data for “Cu are approximate only.)
Fig. 3. Differential energy absorption rate per unit mass thickness (in units of absorbed dose rate unity activity x area) spherical shell of radius x (41rx2R/A ) from a point source of *‘Cu, 97R~, ‘O”Pd,and ““‘WI.
is
becomes the amount of energy deposited per unit thickness in a spherical shell of radius r per unit time per unit activity and nullifies the l/r’ dependence. Figures 3 and 4 give the results of this calculation. From these figures it can be seen that “‘I and 67Cu are relatively long range /I-ray emitters, several hundred micrometers, whereas ‘19Sb,for example, has its major radiation dose contribution in less than 10 pm or approximately one mammalian-cell diameter. To provide a more quantitative measure of the range characteristics of each radionuclide, the integrals over r of the curves in Figs 3 and 4 were also calculated. This quantity, X rlrrr$dr, s0 log
J
IO' i
lo-’ 10-3
I
10-4 lo-'
-_-__ 731,
--______
r91np
\
-*.\,
1,
‘\
\ ‘\.:I, ‘%.
J
10-2
IO-'
1
10
IO2
IO3
104
Fig. 4. Differential energy absorption rate per unit mass thickness (in units of absorbed dose rate per unit activity x area) spherical shell of radius x (4nx2R/A) from a point source of “‘Sb, ‘% “‘1, and 19’Hg.
Radiation absorbed dose estimates of electron emitters
887
--._-._-.‘00p~
i 10-Z
1
Y____j I
....,I
10-l
10
102
10'
10-l
10-2
104
I I
10
102
103
jo4
w
Fig. 6. Integral energy absorption rate in a unit density sphere of radius x (in units of dose rate per unit
Fig. 5. Integral energy absorption rate in a unit density sphere of radius x (in units of dose rate per unit activity x sphere volume), up to radius x
activity x sphere volume), up to radius x
from a point source of ‘19Sb, IrJI, “‘I, and IP7Hg.
from a point source of 6’Cu9“Ru 1 ‘qd 9 and IoimRh. for all isotopes, and thus it was defined as the 100% distance. We fee.1that in this way a similarity to the percentile distance definition is preserved, while including the short-range photon contribution. As a summary for comparison purposes, Table 2 shows the values of xlo, xl5 and x,, accompanied with the dose rates per unit activity (in rad.s-‘.pCi-‘) at these distances. It is clear that ‘19Sb delivers most of its energy within subcellular distances, and accordingly, is not suitable for therapeutic processes that do not allow the radioactive substance to penetrate the cell-such as radioimmunotherapy(‘3)-for cells of diameters in the order of 10 pm. Table 2 also indicates that 19’Hg and ‘“Pd are nearly equivalent in range, by depositing 90% of the available energy in about 6 cell diameters. The difference between these two lies in the dose rates, which are -3 to 4 times larger for 19’Hg than for ‘O”Pdat x,. This indicates that for therapy, 19’Hg would be preferable unless the higher energy y rays of ““‘Pd are needed for monitoring purposes (see Table 1). lz31 can be considered a medium-range source, whereas 67Cu, 97R~ and “lmRh are of the longer range, sparsely-distributed dose type. Although 67Cu and 97R~ have somewhat similar percentile distances, the dose rate from 67Cu is 20 times larger than that
of 97Ru at 600 pm (w 60 cell diameters). Radiation confinement requirements, as well as production facilities and radiobiological factors must be taken into consideration in choosing among these two. ‘OlmRhhas mixed characteristics of short and long range radiation. It deposits 50% of its energy within 5 pm (which may not have radiotoxic effect)(‘” while its 90% distance is about 77 cell diameters (although the absorbed dose rate is quite low at x+,). A direct comparison between “‘I and 67Cu in Table 2 reveals their similarity, which can also be seen in Figs 1 and 2. The chief differences are in their half-lives and y-ray content, which make ‘j’Cu preferable for radioimmunotherapy. The radionuclides discussed above are already available from nuclear reactors (13’1) or spallation reactions C’Cu), or can be produced in a mediumenergy cyclotron. The nuclear reactions proposed for their production are given in Table 3. For each radionuclide a radiochemical labeling procedure is envisaged@’ but will not be discussed here. The present calculations were obtained via a computer program which calculates the quantity R/A and 4rcx*R/A and its radial integral directly from the energy-dissipation distributions of Spencer.(@ Input data for any radionuclide are the conversion- and Auger-electron spectra or /?-ray spectra, and the
Table 2. The distances (x) in micromeren for Wo/ 75%. and WA of the energy 10 be deposited up 10 I mmfrom a point source are lismd for the radioauclides studied. Ah shown are the values of absorbed dose rate in tads-’ pCi_’ at the respective distances. ‘OLafi Ul* q “cu 9’RU ‘qd ‘%b lnHg h Olm) ~~3 (pm) xw (/cm) R:A(xSO) R/A(x75) RIA(x90)
180 370 571 0.365 0.055 0.012
120 271 613 0.054 0.015 0.0004
25.6 38.3 57.4 52.2 22.3 2.26
4.80 422 767 -1156 0.001 0.0003
3.55 5.12 6.47 11720 6530 2420
82.7 131 249 0.558 0.282 0.006
263 493 713 0.165 0.030 0.009
31.1 43.3 55.1 52.9 28.9 9.54
JOHN A. JUNGERMAN et al.
888
Proc. Int. Symp. Shorter-Lived
Table 3. Production methods WJ P,RuW
Spallation
l-d”‘% lOl~~“O,
‘:$Wp.W’$F’d ,J’d(p.xn)‘:;Ag + ‘pd + ‘“:“;Rb
“‘Sb 12q,ll,
‘~~Sqp,3n)‘gre - ‘:$b. r)‘“&(p,50)‘~~e “‘l(p,Sn)‘~Xc + ‘“I
“II
Fission product
‘P’Hg
‘9*u(p.nYqg$-ig
‘O*RII(~,~TII)~RU
+ ‘$Sb
photon contribution. The availability of such a program, which produces absorbed dose data almost directly from a decay scheme, should facilitate future decisions concerning radionuclide choice that may arise because of new chemical, biological or medical information. Mcnowledgemenrs-It is a pleasure to acknowledge helpful conversations with Drs G. L. JlkNardo. S. J. DeNardo, H. H. Hines and M. C. Lagunas-Solar. Support from DOE Grant DE AT03-82 (S. J. DeNardo, principal investigator) is also gratefully acknowledged.
References I. DeNardo S. J., Jungerman J. A., DeNardo G. L., Lagunas-Solar
M. C., Cole W. C. and Meares C. F.
Radionuclides, Washinaton. D.C.. Mav 1982. DOE Conf. 820523 ORNL 19ii3. In press. ’ 2. Bale W. F., Spar J. S. and Goodland R. L. Cancer Res. 65, 779-793 (1960). 3. Lederer C. M. and Shirley V. S. (Eds) Table of Isotopes. (John Wiley, New York, 1978). 4. Bergstrom I. and Nordling C. In Afpha, Beta, and Gamma-Ray Spectroscopy. Siegbahn K. (Ed.) Vol. 2, pp. 1523-1543 (North Holland, Amsterdam, 1965). 5. Berger M. J. Nat. Bur. Stand. Report NBSIR 73-107, Feb. (1973). 6. Spencer L. V. Nat. Bur. Stand. Monogr. No. 1 (1959). 7. Evans R. D. The Atomic Nucleus. p. 714 (McGraw-Hill, 1955). 8. Lagunas-Solar M. C. Cracker Nuclear Laboratory, University of California, Davis, CA. Private communication. 9. Lagunas-Solar M. C.. Avila M. J., Navarro N. J. and Johnson P. C. Jnr. J. Appl. Radiat. Jsot. 35. 743 (1984). IO. Lagunas-Solar M. C.. Wilkins S. R. and Paulson‘D. W. J. Radioanal. Chem. 68. 245 I 19821.
Il. Wilkins S. R., ShimoseS. T.,‘Hines H. H., Jungerman J. A., Hegedus F. and DeNardo G. L. Int. J. Appl. Radiat. Isot. 26, 279 (1975). 12. Browne E. Lawrence Berkeley Laboratory,
University of California, Berkeley, CA. Private communication. 13. Kassis A. I., Adelstein S. J.. Haydock C. and Sastry S. R. J. Nucl. :Med. 24, 1164-1175 (1983).