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Practical assessment of radiation doses using labelled antibodies for therapy
Nucl. Med. Biol. Vol. 13, No. 4, pp. 437-446. hr. J. Radiat. AppI. Insmm. Part B
1986
0883-2897/86
$3.00
+ 0.00
Copyright 0 1986Pergamon Journals Ltd
Printed in Great Britain. All rights reserved
Practical Assessment of Radiation Doses using Labelled Antibodies for Therapy M. J. MYERS,
A. A. EPENETOS
and
G. HOOKER
Departments of Medical Physics and Radiotherapy, Hammersmith Hospital, London WI2 OHS, England
For safe therapy with radiolabelled antibodies it is essential to maximise the uptake of radionuclide in the tumor compared with normal tissue. This paper outlines the methods and limitations of establishing the dosimetry before administering the therapeutic dose. Whole body distributions and kinetics arc established using quantitative radionuclide scanning techniques, single photon tomography and blood counts in conjunction with images from other modalities such as x-ray CT. Our experience with about 40 therapeutic cases, involving mostly intracavity administration, will be outlined.
Introduction Radioactive antibodies that can target onto a tumor and destroy it with localised short range destructive radiation without harming the rest of the body have long been a goal in the field of radiotherapy. Unfortunately, when simply injected into the body, these “magic bullets” have more of a shrapnel effect since the blood carries most of the radiation to normal organs such as the liver and bone marrow. The activity that finally reaches the tumor target is perhaps of the order of 0.01% of the administered dose per gram (unpublished data), impractical for treatment unless the injected activity is increased to unacceptably high levels. The situation is thus similar to but somewhat worse than that found in the established treatment of metastatic thyroid disease using r3’I where perhaps 0.1% of the injected dose might reach the tumor. In both cases i.v. injection and general distribution of radioactive 13’1result in whole body doses of about 1 cGy/lOO MBq administered (1 rad/3 mCi) assuming a half life for body excretion of about a day. In a typical case a thyroid metastasis would retain about 4MBq (100 PCi) per gram from an administered 4 GBq (100 mCi) with about a 4 day half life. This would lead to a tumor radiation dose of 12OOcGy. In contrast the antibody label would deliver only one-tenth of this dose to the tumor. Thus a 5-10 GBq (150-300 mCi) systemic administration of 13’1might be contemplated for thyroid therapy but not, under the above assumptions, thought worthwhile for antibody therapy. We have therefore, while still researching improvements in the general technique of systemic injection, developed another, though rather more limited, strategy of administration. We have narrowed the scope of antibody therapy to treating restricted sys437
terns in the body-cavities such as the peritoneum, pericardium and pleura where all the administered radioactivity can be immediately confined to one body compartment. Thus normal tissues are not allowed access to the antibody which is subsequently actively taken up by the tumor tissue inside the compartment due to the action of the antibody (Fig. I). The result is an efficient method of therapy. This approach may be contrasted with more conventional, non-specific methods of radionuchde cavity therapy involving uniform layering and irradiation of all the cavity surfaces with radionuclides such as “P.“) In all types of administration the dose to tumor and to normal tissue has to be determined or assessed before therapy proceeds, and the substance of this paper is the practical approach to measuring the expected radiation dose. A number of “tumor associated” antibodies have been made available to us by the Imperial Cancer Research Fund in London, England. These include HMFG2, AUAl, K9 and H17E2. As the name suggests the antibodies are not totally specific for individual tumors but are associated with certain kinds of cell structures in tumour (Fig. 2). The actual specificity has been demonstrated from biopsy samples of tumor and normal tissues and from quantitative imaging using different radionuclides attached to specific and to non-specific antibodies imaged simultaneously. The antibodies have, up to now, been labelled with 13’1because of its convenient availability, using a simple efficient iodogen based procedure to produce a sterile pyrogen-free material.
Methods In order to administer the therapeutic doses safely, a method must be developed for estimating the
438
M. .I. MYERSet al.
radiation dose likely to be received by the tumor and by any of the normal organs that may be affected by the radiations that penetrate outside the cavity. The tumor dose may then be maximised commensurate with the normal tissue dose being kept below an acceptably safe level. The dosimetric calculations require a knowledge of: (i) the physical properties of the radionuclide attached to the antibody-the radionuclide may have a number of associated radiations with different energies and consequently different penetrating powers in tissue (ii) the duration of stay within the body of the radioactivity-the radionuclide has a limited physical life and will also be slowly eliminated by the biologic functions of the body (iii) the distribution of the radionuclide-how much of the original radioactivity goes to each part of the body. The exact size of the region where the activity accumulates must be measured and, if the use of radiation with a very limited range is contemplated or if the tumor is relatively large and possibly not completely or uniformly perfused, the distribution of the labelled antibody within the tumor mass itself must be estimated. The above data can be assembled, using the patient as their own control and assuming that later conditions do not change, in a preliminary “diagnostic” study some days prior to administering the therapeutic dose. For this study the antibody is labelled either with a relatively small amount of the therapeutic agent (about 1% of the projected activity) or with a short-lived isotope of the therapeutic agent (e.g. ‘23Iwith a half life of 13 h is used instead of “‘I with a half life of 8 d). The distribution and time course of the activity can then be followed over time with no real danger to the patient. Of the required parameters the physical properties of the radionuclide are perhaps the easiest to determine accurately as long as conventional labels such as r3’I are used. Here the penetrating power of the radiation into most tumors does not require a complicated microdosimetric calculation and conventional formulations of the radiation dosimetry may therefore be applied.(*) These tabulate the internal radiation dose directly in terms of rad/mCi-h (Fig. 3). Microdosimetry would be needed if perhaps more efficient but lower-energy radiations with a range of the order of the dimensions of the tumor cells involved are used. The duration of stay and the spatial distribution of the radioactivity are both investigated by sequential, timed quantitative imaging. By quantitative imaging is meant not just obtaining relative numbers over different sites in the body but a true estimate of the activity measured in Bq at each site. The patient is imaged over a period of days, if a relatively short lived radionuclide like ‘23I is employed, or up to a week if 13’1is the label, since the uptake of the labeled antibody does not establish itself until a couple of
b
a
20
40
60
80
100
120
140
160
180
) Fig. 3. Idealised plot of absorbed radiation dose per unit cumulative activity against target mass. Weight
of
target
(g
days after administration. Quantitation requires an additional mapping of the distribution of attenuation of the body (corresponding exactly to the mapping of the activity distribution) in order to apply a suitable correction to the count rate data for the different amounts of absorption of the radiation in the body. Previously established calibration figures to convert count rate data for a particular set of imaging conditions to activities can then be applied. Practical procedure followed. Activity measurements A scanning large-field-of-view camera fitted with a parallel hole collimator is used to obtain first an anterior and then a posterior view of the whole body (Fig. 4). This process takes about 50 min to complete and is carreid out at 1,24,48 h and at some days after the administration (Fig. 5). Images are recorded and analysed using a standard nuclear medicine computing system. If attenuation measurements are to be included, these are made using a large 57Co disk source with a different and distinguishable energy from the radionuclide labelling the antibody. The disk is transported under the couch moving with the camera which thus views the source through the patient along the whole length of the scan. The transmission whole body image is compared with an unattenuated image obtained in the same way but without the patient to produce the appropriate attenuation factors. The sets of computer images each taken at different times are aligned using a special computer program. This facilitates the setting up of regions of interest over the tumor and the normal organs where the radiation dose has to be calculated. The region is defined using a tracker ball controlled edge detector program (Fig. 6). For measurement of absolute uptakes counts within the regions of interest, the images are anterior, posterior and attenuation combined.“) For determining the kinetics of the distribution only the uptakes relative to the first image are required. Then only the geometric mean of the
‘ZI /(VP uo (q) pue maId
aql u! sal!s laO.w olu! 0 dep (e) uo Lpoqyw
pallaqe[
I,~, palas!u!urpl?
Qvauol!Jademy
JO uognqys!pal
a+lDV ‘1 %j
Fig. 2. Autoradiograph
of labelled
antibody
HMFG2
showing
uptake
at the periphery
of tumor
cells.
Fig, 4. Whole body images of ‘,‘I labelled monclonai antibody obtained by scanning under and over the patient. The apparent differences in uptake distribukion reflect the different effects of attenuation of the detected radiation throughout the body.
440
441
P
Fig. 10. Anterior,
posterior,
Fig. 1 I. Part of a sequence
left and right lateral planar antibody.
of sectional
camera
images of pericardial
images made at I3 mm intervals distribution as Fig. 10.
through
uptake
of labelled
the same pericardial
Fig. 12. One of a sequence of x-ray CT sectional images of the pericardium shown in Figs 10 and showing the anatomy in more detail and enabling a better estimate of the volume of distribution.
Fig. 13. x-Ray
CT images
used to assess the effects of treatment on the size of a gloima. size of tumor after treatment may be seen.
443
Reduction
1I
of
Fig.
14. NMR
images
of glioma
demonstrating
another volume.
444
technique
of accurately
defining
the tumor
Assessment of radiation doses Actiwty
m abdomen
phase
I
445
clearance
100.
t .““.w..
physical
Ih
dewy .. . . . . . . . . .
.\” c3
0
u In
10. :
-I
I
I
100 Hours
after
200
injection
Fig. 7. Plot of the geometric mean of counts within regions of interest on anterior and posterior images as a function of time, used to determine the lifetime of the labelled antibody in the target in the preliminary diagnostic phase of the treatment.
100
260
300
Volume
400
500
600
(mL)
Fig. 9. Result of calibration showing that over a whole range of volumes and thicknesses of attenuator the calibration factor is constant within k 5%.
Determination of volumes of distribution anterior interest
and posterior counts within the regions of is used without correction for attenuation
and plotted as a function of time (Fig. 7). Calibration of equipment A set of calibration factors will have been previously obtained by scanning over a phantom rather than the patient. The phantom consists of a large plastic tank filled to different extents with water to simulate different body thicknesses in which are placed a series of different sources of known activities but with a range of sizes to simulate the different organs encountered (Fig. 8). For the phantom a good approximation ( + 5%) to the absolute activity in the sources is found over a wide range of thicknesses of attenuating material, source sizes and depths using a simplified method of calculation (Fig. 9). It is not, however, possible to carry through this relatively good accuracy in the patient measurements for reasons outlined below.
lFig. 8. Method of calibrating equipment to obtain absolute quantitation of uptake of activity. The plastic box is filled to different depths with water and a series of volumes of known activity at a number of positions scanned and counted.
Additional single views of individual organs and tumour sites with better definition than the whole body images are obtained to help determine the size of the tumor (Fig. 10). However, since the resolutions of a centimetre or two even for these images are inadequate, other imaging techniques are also employed. These include single photon emission computed tomography in which the camera is rotated and a series of images at different angles is acquired around the patient. The views are combined to produce another set of computer generated images that show the radionuclide distribution over thin sections of the body (Fig. 11). Although this tomographic technique helps avoid the obscuring effects of overlying and underlying tissue background and increases the contrast with which the target is seen it does not improve the resolution of the image below about 2cm and does not solve the problem of accurately defining the volume of distribution. x-Ray computed tomography, nuclear magnetic resonance imaging and ultrasound scanning, all yielding resolutions of a millimetre or so have to be employed in order to define accurately the extent of the tumor (Figs 12, 13 and 14). These anatomical imaging techniques do not, however, provide the functional uptake information derived from the radiolabelled antibody imaging. Estimates of the tumor volume from radionuclide imaging are very unrealiable since the linear dimensions extracted from the planar images have to be cubed for the volume determination. Even a point appears blurred by the poor resolution of the technique and will appear as having a dimension of l-2cm. When this is taken into account a linear measure of 2 cm (associated with 4-5 g tumor) might have an error of 0.5 cm (25%) so that the volume/mass will have an error of about 75%, leading to an error contribution of this magnitude in the final dose estimate. For larger tumors, say a 50 g mass of linear extent 4.5 cm, the error in the volume
446
M. J. MYERS ef al. Acf~v~fy
I”
abdomen
phase
PhysICOf
II
clearance
decay
I
I
I
I
1
1
I
1
2
3
4
5
6
7
Days
after
therapy
Fig. 15. Kinetics of labelled antibody over tumor administration of the therapeutic dose, used to
site after
check the
predictions of the diagnostic phase. and dose estimate for the radionuclide image will both decrease to about 33%. The ultrasound, MR or x-ray CT images will thus improve the accuracy considerably. Dosimetric calculations
With the size of the tumor estimated, the time course of the activity established and the properties of the radionuclide (13’1) known, the radiation dose to the target may be calculated using standard MIRD techniques.(5*6)Doses to the blood, whole body and to selected organs also follow the same treatment though assumptions about the relative location of the main organs (e.g. the spatial relationship of the liver with respect to a tumor in the peritoneum) may have to be made. After the dosimetric calculations have been completed, the administered activity is scaled up until a therapeutic dose is deliverable to the tumour without potential harm to the patient. A check does, however, have to be made that the conditions found in the diagnostic stage still hold for the therapeutic stage. This is achieved by subsequent imaging, counting and sampling over a period of weeks after the therapeutic dose has been administered. Imaging may be performed with a low sensitivity rectilinear scanner since therapeutic activities would overwhelm the sensitive scintillation camera for the first week or so. Blood and urine sampling is also carried out. Timed counting over the therapy site with a hand held collimated detector or ionisation chamber dosimeter also provide checks that elimination rates of the activity are roughly the same in the diagnostic and therapeutic phases of the procedure (Fig. 15).
Results The 40 therapeutic studies analysed up to this date include 8 pleural, 21 peritoneal and 2 pericardial
cavities, 4 intravenous and 4 intraarterial administrations of the three types of “‘1 labelled antibody. There was a wide variation in the rate of loss of activity measured over each individual site and in the blood samples. For the peritoneum where ascites were present the biological half life (when the measurements were fitted to a single exponential approximating the clearance) ranged over 4G-60 h: without ascites the range was 3(r50 h. For the pleural cavities the range of half-live was 30-90 h and for the pericardium a half life of 70 h was measured. In a typical case of a pericardium, for a mass of 100 g and a 60 h half life, the administration of 1 GBq (30mCi) of i3’I labelled antibody resulted in a dose of 9000 cGy. For smaller masses, estimated at say 10 g in the peritoneum, with a 30 h half life the 1 GBq distributed throughout the cavity but concentrating in the tumor would also deliver a tumor dose of 9000 cGy. The error in the dose estimated is large, reflecting mostly the unknown size of the target. Doses to adjacent normal organs such as the liver are in the range of 20 cGy though in extreme cases may extend to 200 cGy. We have used the technique for treatment of, among others, stage III and stage IV ovarian tumors and gliomas, often where conventional chemo- and radiotherapy have been attempted without success. We have produced consistent remission or reduction of tumor growth over periods of up to 18 months. Toxic effects in the case of peritoneal administration for ovarian cancers has been confined to mild diarrhoea. The technique, while obviously still under development, promises to provide an effective alternative to more conventional methods of therapy with radionuclides, such as that using “P colloids. This comparative aspect is being investigated as is the use of antibodies labelled with radionuchdes possessing different properties and ranges in tissue, such as 9oy and 32P.
References 1. Boye
E., Lindegaard Davy and Jakobsen
M. W., Pause E., Skretting A., E. Br. J. Radiol. 57, 395 (1984). 2. MIRD Pamphlet No. I1 (Society of Nuclear Medicine, New York, 1975). 3. Myers M. J., Lavender J. P., deohverira J. B. and Maseri A. Br. J. Radiol. 54. 1062 (1981). 4. Leichner P. K., Klein J. L., Garrison J. B., Jenkins R. E., Nickoloff E. L., Ettinger D. S. and Order S. E.
Int. J. Radiat. Oncol. Biol. Phys. 7, 323 (1981). 5. Wessels B. W. and Rogus R. D. Med. Phys. 11, 638 (1984).
1986
0883-2897/86
$3.00
+ 0.00
Copyright 0 1986Pergamon Journals Ltd
Printed in Great Britain. All rights reserved
Practical Assessment of Radiation Doses using Labelled Antibodies for Therapy M. J. MYERS,
A. A. EPENETOS
and
G. HOOKER
Departments of Medical Physics and Radiotherapy, Hammersmith Hospital, London WI2 OHS, England
For safe therapy with radiolabelled antibodies it is essential to maximise the uptake of radionuclide in the tumor compared with normal tissue. This paper outlines the methods and limitations of establishing the dosimetry before administering the therapeutic dose. Whole body distributions and kinetics arc established using quantitative radionuclide scanning techniques, single photon tomography and blood counts in conjunction with images from other modalities such as x-ray CT. Our experience with about 40 therapeutic cases, involving mostly intracavity administration, will be outlined.
Introduction Radioactive antibodies that can target onto a tumor and destroy it with localised short range destructive radiation without harming the rest of the body have long been a goal in the field of radiotherapy. Unfortunately, when simply injected into the body, these “magic bullets” have more of a shrapnel effect since the blood carries most of the radiation to normal organs such as the liver and bone marrow. The activity that finally reaches the tumor target is perhaps of the order of 0.01% of the administered dose per gram (unpublished data), impractical for treatment unless the injected activity is increased to unacceptably high levels. The situation is thus similar to but somewhat worse than that found in the established treatment of metastatic thyroid disease using r3’I where perhaps 0.1% of the injected dose might reach the tumor. In both cases i.v. injection and general distribution of radioactive 13’1result in whole body doses of about 1 cGy/lOO MBq administered (1 rad/3 mCi) assuming a half life for body excretion of about a day. In a typical case a thyroid metastasis would retain about 4MBq (100 PCi) per gram from an administered 4 GBq (100 mCi) with about a 4 day half life. This would lead to a tumor radiation dose of 12OOcGy. In contrast the antibody label would deliver only one-tenth of this dose to the tumor. Thus a 5-10 GBq (150-300 mCi) systemic administration of 13’1might be contemplated for thyroid therapy but not, under the above assumptions, thought worthwhile for antibody therapy. We have therefore, while still researching improvements in the general technique of systemic injection, developed another, though rather more limited, strategy of administration. We have narrowed the scope of antibody therapy to treating restricted sys437
terns in the body-cavities such as the peritoneum, pericardium and pleura where all the administered radioactivity can be immediately confined to one body compartment. Thus normal tissues are not allowed access to the antibody which is subsequently actively taken up by the tumor tissue inside the compartment due to the action of the antibody (Fig. I). The result is an efficient method of therapy. This approach may be contrasted with more conventional, non-specific methods of radionuchde cavity therapy involving uniform layering and irradiation of all the cavity surfaces with radionuclides such as “P.“) In all types of administration the dose to tumor and to normal tissue has to be determined or assessed before therapy proceeds, and the substance of this paper is the practical approach to measuring the expected radiation dose. A number of “tumor associated” antibodies have been made available to us by the Imperial Cancer Research Fund in London, England. These include HMFG2, AUAl, K9 and H17E2. As the name suggests the antibodies are not totally specific for individual tumors but are associated with certain kinds of cell structures in tumour (Fig. 2). The actual specificity has been demonstrated from biopsy samples of tumor and normal tissues and from quantitative imaging using different radionuclides attached to specific and to non-specific antibodies imaged simultaneously. The antibodies have, up to now, been labelled with 13’1because of its convenient availability, using a simple efficient iodogen based procedure to produce a sterile pyrogen-free material.
Methods In order to administer the therapeutic doses safely, a method must be developed for estimating the
438
M. .I. MYERSet al.
radiation dose likely to be received by the tumor and by any of the normal organs that may be affected by the radiations that penetrate outside the cavity. The tumor dose may then be maximised commensurate with the normal tissue dose being kept below an acceptably safe level. The dosimetric calculations require a knowledge of: (i) the physical properties of the radionuclide attached to the antibody-the radionuclide may have a number of associated radiations with different energies and consequently different penetrating powers in tissue (ii) the duration of stay within the body of the radioactivity-the radionuclide has a limited physical life and will also be slowly eliminated by the biologic functions of the body (iii) the distribution of the radionuclide-how much of the original radioactivity goes to each part of the body. The exact size of the region where the activity accumulates must be measured and, if the use of radiation with a very limited range is contemplated or if the tumor is relatively large and possibly not completely or uniformly perfused, the distribution of the labelled antibody within the tumor mass itself must be estimated. The above data can be assembled, using the patient as their own control and assuming that later conditions do not change, in a preliminary “diagnostic” study some days prior to administering the therapeutic dose. For this study the antibody is labelled either with a relatively small amount of the therapeutic agent (about 1% of the projected activity) or with a short-lived isotope of the therapeutic agent (e.g. ‘23Iwith a half life of 13 h is used instead of “‘I with a half life of 8 d). The distribution and time course of the activity can then be followed over time with no real danger to the patient. Of the required parameters the physical properties of the radionuclide are perhaps the easiest to determine accurately as long as conventional labels such as r3’I are used. Here the penetrating power of the radiation into most tumors does not require a complicated microdosimetric calculation and conventional formulations of the radiation dosimetry may therefore be applied.(*) These tabulate the internal radiation dose directly in terms of rad/mCi-h (Fig. 3). Microdosimetry would be needed if perhaps more efficient but lower-energy radiations with a range of the order of the dimensions of the tumor cells involved are used. The duration of stay and the spatial distribution of the radioactivity are both investigated by sequential, timed quantitative imaging. By quantitative imaging is meant not just obtaining relative numbers over different sites in the body but a true estimate of the activity measured in Bq at each site. The patient is imaged over a period of days, if a relatively short lived radionuclide like ‘23I is employed, or up to a week if 13’1is the label, since the uptake of the labeled antibody does not establish itself until a couple of
b
a
20
40
60
80
100
120
140
160
180
) Fig. 3. Idealised plot of absorbed radiation dose per unit cumulative activity against target mass. Weight
of
target
(g
days after administration. Quantitation requires an additional mapping of the distribution of attenuation of the body (corresponding exactly to the mapping of the activity distribution) in order to apply a suitable correction to the count rate data for the different amounts of absorption of the radiation in the body. Previously established calibration figures to convert count rate data for a particular set of imaging conditions to activities can then be applied. Practical procedure followed. Activity measurements A scanning large-field-of-view camera fitted with a parallel hole collimator is used to obtain first an anterior and then a posterior view of the whole body (Fig. 4). This process takes about 50 min to complete and is carreid out at 1,24,48 h and at some days after the administration (Fig. 5). Images are recorded and analysed using a standard nuclear medicine computing system. If attenuation measurements are to be included, these are made using a large 57Co disk source with a different and distinguishable energy from the radionuclide labelling the antibody. The disk is transported under the couch moving with the camera which thus views the source through the patient along the whole length of the scan. The transmission whole body image is compared with an unattenuated image obtained in the same way but without the patient to produce the appropriate attenuation factors. The sets of computer images each taken at different times are aligned using a special computer program. This facilitates the setting up of regions of interest over the tumor and the normal organs where the radiation dose has to be calculated. The region is defined using a tracker ball controlled edge detector program (Fig. 6). For measurement of absolute uptakes counts within the regions of interest, the images are anterior, posterior and attenuation combined.“) For determining the kinetics of the distribution only the uptakes relative to the first image are required. Then only the geometric mean of the
‘ZI /(VP uo (q) pue maId
aql u! sal!s laO.w olu! 0 dep (e) uo Lpoqyw
pallaqe[
I,~, palas!u!urpl?
Qvauol!Jademy
JO uognqys!pal
a+lDV ‘1 %j
Fig. 2. Autoradiograph
of labelled
antibody
HMFG2
showing
uptake
at the periphery
of tumor
cells.
Fig, 4. Whole body images of ‘,‘I labelled monclonai antibody obtained by scanning under and over the patient. The apparent differences in uptake distribukion reflect the different effects of attenuation of the detected radiation throughout the body.
440
441
P
Fig. 10. Anterior,
posterior,
Fig. 1 I. Part of a sequence
left and right lateral planar antibody.
of sectional
camera
images of pericardial
images made at I3 mm intervals distribution as Fig. 10.
through
uptake
of labelled
the same pericardial
Fig. 12. One of a sequence of x-ray CT sectional images of the pericardium shown in Figs 10 and showing the anatomy in more detail and enabling a better estimate of the volume of distribution.
Fig. 13. x-Ray
CT images
used to assess the effects of treatment on the size of a gloima. size of tumor after treatment may be seen.
443
Reduction
1I
of
Fig.
14. NMR
images
of glioma
demonstrating
another volume.
444
technique
of accurately
defining
the tumor
Assessment of radiation doses Actiwty
m abdomen
phase
I
445
clearance
100.
t .““.w..
physical
Ih
dewy .. . . . . . . . . .
.\” c3
0
u In
10. :
-I
I
I
100 Hours
after
200
injection
Fig. 7. Plot of the geometric mean of counts within regions of interest on anterior and posterior images as a function of time, used to determine the lifetime of the labelled antibody in the target in the preliminary diagnostic phase of the treatment.
100
260
300
Volume
400
500
600
(mL)
Fig. 9. Result of calibration showing that over a whole range of volumes and thicknesses of attenuator the calibration factor is constant within k 5%.
Determination of volumes of distribution anterior interest
and posterior counts within the regions of is used without correction for attenuation
and plotted as a function of time (Fig. 7). Calibration of equipment A set of calibration factors will have been previously obtained by scanning over a phantom rather than the patient. The phantom consists of a large plastic tank filled to different extents with water to simulate different body thicknesses in which are placed a series of different sources of known activities but with a range of sizes to simulate the different organs encountered (Fig. 8). For the phantom a good approximation ( + 5%) to the absolute activity in the sources is found over a wide range of thicknesses of attenuating material, source sizes and depths using a simplified method of calculation (Fig. 9). It is not, however, possible to carry through this relatively good accuracy in the patient measurements for reasons outlined below.
lFig. 8. Method of calibrating equipment to obtain absolute quantitation of uptake of activity. The plastic box is filled to different depths with water and a series of volumes of known activity at a number of positions scanned and counted.
Additional single views of individual organs and tumour sites with better definition than the whole body images are obtained to help determine the size of the tumor (Fig. 10). However, since the resolutions of a centimetre or two even for these images are inadequate, other imaging techniques are also employed. These include single photon emission computed tomography in which the camera is rotated and a series of images at different angles is acquired around the patient. The views are combined to produce another set of computer generated images that show the radionuclide distribution over thin sections of the body (Fig. 11). Although this tomographic technique helps avoid the obscuring effects of overlying and underlying tissue background and increases the contrast with which the target is seen it does not improve the resolution of the image below about 2cm and does not solve the problem of accurately defining the volume of distribution. x-Ray computed tomography, nuclear magnetic resonance imaging and ultrasound scanning, all yielding resolutions of a millimetre or so have to be employed in order to define accurately the extent of the tumor (Figs 12, 13 and 14). These anatomical imaging techniques do not, however, provide the functional uptake information derived from the radiolabelled antibody imaging. Estimates of the tumor volume from radionuclide imaging are very unrealiable since the linear dimensions extracted from the planar images have to be cubed for the volume determination. Even a point appears blurred by the poor resolution of the technique and will appear as having a dimension of l-2cm. When this is taken into account a linear measure of 2 cm (associated with 4-5 g tumor) might have an error of 0.5 cm (25%) so that the volume/mass will have an error of about 75%, leading to an error contribution of this magnitude in the final dose estimate. For larger tumors, say a 50 g mass of linear extent 4.5 cm, the error in the volume
446
M. J. MYERS ef al. Acf~v~fy
I”
abdomen
phase
PhysICOf
II
clearance
decay
I
I
I
I
1
1
I
1
2
3
4
5
6
7
Days
after
therapy
Fig. 15. Kinetics of labelled antibody over tumor administration of the therapeutic dose, used to
site after
check the
predictions of the diagnostic phase. and dose estimate for the radionuclide image will both decrease to about 33%. The ultrasound, MR or x-ray CT images will thus improve the accuracy considerably. Dosimetric calculations
With the size of the tumor estimated, the time course of the activity established and the properties of the radionuclide (13’1) known, the radiation dose to the target may be calculated using standard MIRD techniques.(5*6)Doses to the blood, whole body and to selected organs also follow the same treatment though assumptions about the relative location of the main organs (e.g. the spatial relationship of the liver with respect to a tumor in the peritoneum) may have to be made. After the dosimetric calculations have been completed, the administered activity is scaled up until a therapeutic dose is deliverable to the tumour without potential harm to the patient. A check does, however, have to be made that the conditions found in the diagnostic stage still hold for the therapeutic stage. This is achieved by subsequent imaging, counting and sampling over a period of weeks after the therapeutic dose has been administered. Imaging may be performed with a low sensitivity rectilinear scanner since therapeutic activities would overwhelm the sensitive scintillation camera for the first week or so. Blood and urine sampling is also carried out. Timed counting over the therapy site with a hand held collimated detector or ionisation chamber dosimeter also provide checks that elimination rates of the activity are roughly the same in the diagnostic and therapeutic phases of the procedure (Fig. 15).
Results The 40 therapeutic studies analysed up to this date include 8 pleural, 21 peritoneal and 2 pericardial
cavities, 4 intravenous and 4 intraarterial administrations of the three types of “‘1 labelled antibody. There was a wide variation in the rate of loss of activity measured over each individual site and in the blood samples. For the peritoneum where ascites were present the biological half life (when the measurements were fitted to a single exponential approximating the clearance) ranged over 4G-60 h: without ascites the range was 3(r50 h. For the pleural cavities the range of half-live was 30-90 h and for the pericardium a half life of 70 h was measured. In a typical case of a pericardium, for a mass of 100 g and a 60 h half life, the administration of 1 GBq (30mCi) of i3’I labelled antibody resulted in a dose of 9000 cGy. For smaller masses, estimated at say 10 g in the peritoneum, with a 30 h half life the 1 GBq distributed throughout the cavity but concentrating in the tumor would also deliver a tumor dose of 9000 cGy. The error in the dose estimated is large, reflecting mostly the unknown size of the target. Doses to adjacent normal organs such as the liver are in the range of 20 cGy though in extreme cases may extend to 200 cGy. We have used the technique for treatment of, among others, stage III and stage IV ovarian tumors and gliomas, often where conventional chemo- and radiotherapy have been attempted without success. We have produced consistent remission or reduction of tumor growth over periods of up to 18 months. Toxic effects in the case of peritoneal administration for ovarian cancers has been confined to mild diarrhoea. The technique, while obviously still under development, promises to provide an effective alternative to more conventional methods of therapy with radionuclides, such as that using “P colloids. This comparative aspect is being investigated as is the use of antibodies labelled with radionuchdes possessing different properties and ranges in tissue, such as 9oy and 32P.
References 1. Boye
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