Radiolabeled Antibody Tumor Dosimetry

113 Pages·2000·1.45 MB·English

AAPM REPORT NO. 40
RADIOLABELED ANTIBODY
TUMOR DOSIMETRY
REPORT OF
TASK GROUP NO. 2
AAPM NUCLEAR MEDICINE COMMITTEE
Members
Barry W. Wessels, Chairman
A. Bertrand Brill
Donald J. Buchsbaum
Laurence P. Clarke
Darrell R. Fisher
John L. Humm
Timothy K. Johnson
Jerry L. Klein
Kenneth F. Koral
Cheuk S. Kwok
Virginia Langmuir
Peter K. Leichner
Daniel J. Macey
George Sgouros
Jeffry A. Siegel
Edward A. Silverstein
Mike Stabin
Sven-Erik Strand
Evelyn E. Watson
Lawrence E. Williams
Latresla A. Wilson
Ellen D. Yorke
Pat Zanzonico
April 1993
Published for the
American Association of Physicists in Medicine
by the American Institute of Physics
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CONTENTS
Journal Editor’s Preface
JohnS.Laughlin...................................................................................... 497
Co-Editors’ Preface
David A. Weber and Amin I. Kassis........................................................................................................................................ 497
Introduction: Radiolabeled antibody tumor dosimetry
Donald J. Buchsbaum and Barry W. Wessels.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Selection of radionuclides for radioimmunotherapy
Leonard F. Mausner and Suresh C. Srivastava.................................................................................................................. 503
MIRD formulation
Evelyn E. Watson, Michael G. Stabin, and Jeffry A. Siegel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
Pharmacokinetic modeling
Sven-Erik Strand, Pat Zanzonico, and Timothy K. Johnson.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Tumor dosimetry in radioimmunotherapy: Methods of calculation for beta particles
Peter K. Leichnerand Cheuk S. Kwok................................................................................................................................. 529
Microdosimetric concepts in radioimmunotherapy
J. L. Humm, J. C. Roeske, D. R. Fisher, and G. T. Y. Chen.. . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . , . . . . . . . . . . . . . . . 535
Multicellular dosimetry for beta-emitting radionuclides: Autoradiography, thermoluminescent
dosimetry and three-dimensional dose calculations
E. D. Yorke, L. E. Williams, A. J. Demidecki, D. B. Heidorn, P. L. Roberson, and B. W. Wessels.. . . . . . . . . . . . . . . 543
Experimental radioimmunotherapy
Donald J. Buchsbaum, Virginia K. Langmuir, and Barry W. Wessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
An overview of imaging techniques and physical aspects of treatment planning in
radioimmunotherapy
Peter K. Leichner, Kenneth F. Koral, Ronald J. Jaszczak, Alan J. Green, George T. Y. Chen, and
JohnC.Roeske......................................................................................, 569
Radioimmunotherapy dose estimation in patients with B-cell lymphoma
J. A. Siegel, D. M. Goldenberg, and C. C. Badger.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
Dosimetry of solid tumors
Ruby F. Meredith, Timothy K. Johnson, Gene Plott, Daniel J. Macey, Robert L. Vessella, Latresia A. Wilson,
Hazel B. Breitz, and Lawrence E. Williams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Dosimetry of intraperitoneally administered radiolabeled antibodies
John C. Roeske, George T. Y. Chen, and A. Bertrand Brill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Radiobiology of radiolabeled antibody therapy as applied to tumor dosimetry
V. K. Langmuir, J. F. Fowler, S. J. Knox, B. W. Wessels, R. M. Sutherland, and J. Y. C. Wong . . . . . . . . . . . . . . . . . 601
Journal Editor’s Preface
The AAPM, through its Science Council, asked Medical Physics to accept the
responsibility for the scientific review of all of the manuscripts proposed for this report
and to consider the final manuscripts for publication in Medical Physics. This respon-
sibility was accepted by the Editor and Editorial Board. The Editor then asked Dr.
David A. Weber, Associate Editor and Head of Nuclear Medicine Research at the
Brookhaven National Laboratory, and one of his scientific colleagues, Dr. Amin I.
Kassis, Director of Radiation Biology, Brigham and Women’s Hospital, Harvard
Medical School, to accept the responsibility for scientific reviews of the material to be
provided for the report and to serve as the Co-Editors of a special issue of the journal.
This arrangement was approved by the Science Council of the AAPM and by the
Editorial Board.
This review, a major task, has been carried out in a comprehensive and scientifically
rigorous manner by the Editors for this special issue with the vital assistance of the
expert referees, authors and Task Group members. Medical Physics appreciates the
decision of the Task Group to offer this important collection of articles written by
authorities in the field of radiolabeled antibody tumor dosimetry for publication in the
AAPM journal.
John S. Laughlin
Co-Editors’ Preface
Monoclonal antibodies have been considered particularly appealing as selective
carriers of diagnostic and therapeutic radionuclides in vivo. Their target specificity
continues to attract investigators to identify and produce new agents for clinical use.
In spite of the limited number of clinical applications at present, it is extremely
important that factors influencing the localization and clearance properties of radio-
immunoconjugates, especially tumor-associated, antigen-specific antibodies, be consid-
ered and understood by those administering them to patients so as to assess those
variables that influence the absorbed radiation dose from internal emitters. The ab-
sorbed radiation dose has been, and will continue to be, a pivotal factor in assessing the
risks and therapeutic utilities of radiopharmaceuticals.
The AAPM Nuclear Medicine Task Group, under the leadership of Dr. Barry
Wessels, sought qualified experts in various specialties concerned with the dosimetry
of radiolabeled antibodies to develop a well-balanced review of the multiple concerns
and factors that influence the clinical use of radiolabeled anti-tumor antibodies. Dr.
Donald J. Buchsbaum, a member of the Task Group, chaired a subcommittee respon-
sible for coordinating and overseeing the preparation of all manuscripts. In the 13
manuscripts produced, many of the approaches employed to estimate absorbed radi-
ation dose in radioimmunotherapy have been evaluated, and the physical, physiologic,
chemical, and biologic parameters affecting tumor dosimetry presented. In addition,
the decay properties of various radionuclides and their radiobiologic effects have been
discussed, and dose calculations at the organ, tissue, cellular, and subcellular levels
compared. The manuscripts, containing extensive, up-to-date reference lists, will be
very useful to those interested in the use of radiolabeled antibodies in the diagnosis and
treatment of disease.
We are pleased to have had the opportunity to explore with the authors the mul-
tifaceted topic of radiolabeled-antibody tumor dosimetry. Since many of the experts in
this field are contributors to this supplement, it required some extra attention to find
equally qualified referees. Having accomplished this, we would like to express our
sincere gratitude to those who have volunteered their time to review and comment on
the manuscripts.
David A. Weber and Amin I. Kassis
Introduction: Radiolabeled antibody tumor dosimetry
Donald J. Buchsbauma)
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham,
Alabama 35233-6832
Barry W. Wessels
Department of Radiology, George Washington University Medical Center, Washington, DC 20037
(Received 18 March 1992; accepted for publication 8 January 1993)
I. INTRODUCTION diolabeled antibody therapy are essential to support the
development of RIT in the treatment of neoplastic diseases.
Through the sponsorship of the Nuclear Medicine Com- Radiation dosimetry is important for treatment planning
mittee of the American Association of Physicists in Med- and the assessment of results. It is necessary to determine
icine (AAPM), a Nuclear Medicine Task Group 2, “Do- the quantity of radiolabeled antibody to administer to max-
simetry of Radiolabeled Antibodies” was established in imize the radiation dose to the tumor while not exceeding
July 1987 under the Chairmanship of Dr. Barry Wessels to tolerance levels of critical normal tissues, In contrast to
produce reports on radiolabeled antibody dosimetry, which external beam radiation therapy dosimetry, the tumor do-
would include an extensive literature search and an analy- simetry for radiolabeled antibody therapy is dependent on
sis of how to approach the dosimetry to normal tissues and a number of variables including: ( 1) kinetics of biodistri-
tumor of radiolabeled antibody therapy (radioimmuno- bution, tumor uptake and retention of the radiolabeled an-
therapy). The first report published in 19901 summarized a tibody, (2) the uniformity of distribution of the radiola-
“Bone Marrow Dosimetry and Toxicity for Radiolabeled beled antibody within tumor, (3) the radionuclide
Antibodies” symposium held in conjunction with the 1988 attached to the antibody, and (4) the radiobiological re-
American Society for Therapeutic Radiology and Oncol- sponse of tumor cells to continuously decreasing low-dose-
ogy (ASTRO) annual meeting. In 1989, the Steering Com- rate radiation.
mittee on the Nuclear Medicine Task Group 2 decided at The 12 papers in this special issue of Medical Physics
the Society of Nuclear Medicine (SNM) Annual Meeting summarize the problems, various techniques that are being
that the new focus area for the Task Group would be tu- used to estimate the tumor dosimetry associated with ra-
mor dosimetry for radiolabeled antibody therapy. The diolabeled antibody therapy, and future directions as high-
Task Group members and invited guests active in radiola- lighted below.
beled antibody research from the physics, radiation biol-
ogy, nuclear medicine, and oncology communities had
been invited to attend meetings to plan and prepare this II. TOPICS DISCUSSED IN THIS REPORT
report on “Radiolabeled Antibody Tumor Dosimetry.”
A. Selection of radionuclides for RIT
These meetings were held in conjunction with the annual
meetings of the ASTRO, the AAPM, the SNM, the “In- The contribution by Mausner and Srivastava3 to this
ternational Conference on Monoclonal Antibody Immuno- special issue reviews the factors that influence the choice of
conjugates for Cancer” and the “Third Conference on Ra- a radionuclide for RIT. A potential advantage of some of
dioimmunodetection and Radioimmunotherapy of the radionuclides would be a higher tumor/whole-body
Cancer.” The purpose of this report is to provide an exten- dose, resulting in less toxicity to normal tissue, particularly
sive literature search and review the various approaches bone marrow. It is essential to carefully consider the choice
that are being pursued in preclinical and clinical studies to of radionuclide in conjunction with the in vivo pharmaco-
estimate tumor dosimetry associated with radioimmuno- kinetic (localization and clearance in tumor and normal
therapy (RIT), and to suggest future directions for dosim- tissues) properties of the radiolabeled MoAb, the physical
etry research in this field. Included in this report is a dis- half-life of the radionuclide, the chemistry of conjugation
cussion of the radiobiological aspects of tumor dosimetry to MoAbs, and the toxicity of free radionuclide.
of radiolabeled antibody therapy. The choice of radionuclide also depends on the micro-
Radiolabeled monoclonal antibodies (MoAbs) offer the distribution of the radiolabeled MoAb relative to the radi-
potential of highly localized, targeted radiation treatment osensitive target sites, involving uniform versus nonuni-
of cancer. The effectiveness of radiation treatment of ma- form deposition in tumors or localization on cell surfaces
lignant disease is correlated with the total dose delivered, versus internalization of radionuclides to the cell cytoplasm
with increasing dose producing increasing cell kill. Simi- or nuclei.
larly, normal tissue damage is also directly related to the To optimize the efficacy of RIT, it will be necessary to
total dose deposited. The ability to quantify the dose de- develop combinations of MoAbs or antibody fragments
livered to tumor and normal tissues when using radiola- and radionuclides whose pharmacokinetics, physical half-
beled MoAbs has been a perplexing problem. lives and emissions are matched to give the largest possible
As noted in the review of a National Cancer Institute tumor dose and the least normal tissue toxicity, i.e., the
workshop,2 techniques for evaluating the dosimetry of ra- largest possible therapeutic ratio.
499 Med. Phys. 20 (2), Pt. 2, Mar/Apr 1993 0094-2405/93/020499-04$01.20 © 1993 Am. Assoc. Phys. Med. 499
500 D. J. Buchsbaum and B. W. Wessels: Introduction: Radiolabeled antibody tumor dosimetry 500
B. MIRD formulation effect of source microdistribution on individual cells has
been taken by a number of investigators, because of the
The approach developed by the Medical Internal Radi-
limitations of the macroscopic MIRD formulation and the
ation Dose (MIRD) Committee of the Society of Nuclear
nonuniformity of the radiolabeled antibody in tumor.
Medicine for the estimation of average absorbed dose from
Humm et al.7 in this report summarize approaches that
internally deposited radionuclides has been applied to ra-
are being used to estimate the microdosimetry of RIT. It
diolabeled MoAb therapy in animals and humans, as de-
should be noted, however, that microdosimetry estimates
scribed in the paper by Watson et al.4 in this report. The
are based on modeling and are difficult to substantiate ex-
classic MIRD formulation widely used for macroscopic
perimentally.
dosimetry problems assumes a uniform distribution of cu-
mulated activities of radiolabeled MoAbs within each
source region and a uniform deposition of energy within F. Autoradiography, thermoluminescent dosimetry,
and three-dimensional dose calculations
each target region. The experimental animal and clinical
patient studies clearly demonstrate that radiolabeled Radionuclide activity variations within tumors can be
MoAbs are not uniformly distributed within solid tumors. measured by quantitative autoradiography. However,
There are point-source calculations available within the quantitative autoradiography alone cannot provide total
MIRD pamphlets to deal with the problem of dose heter- dose measurements, because of the temporal change in ra-
ogeneity encountered in RIT. diolabeled antibody uptake, penetration, and clearance.’
In addition to the problem of nonuniform uptake of Yorke et al.8 note that autoradiography and thermolu-
radiolabeled MoAbs in solid tumors, the macroscopic minescent dosimetry are complementary techniques. Au-
MIRD approach does not distinguish between a uniform toradiography shows the activity distribution at a particu-
distribution of radiolabeled MoAb that binds to the cell lar point in time, whereas TLDs are integrating dosimeters
surface and a uniform distribution of nonspecific radiola- performing spatial and temporal integrations within the
beled MoAb. volume they occupy, and can be used to calibrate the au-
Conventional MIRD type calculations for radiolabeled toradiographs.
MoAbs give approximate average dose estimates which Griffith et al9 and Roberson et al.10 converted data
may not be sufficiently accurate, especially for alpha and from serial autoradiographs to derive three-dimensional
Auger emitters. With these types of radionuclides, a mi- activity matrices in animal tumor xenografts. Using point
crodosimetric approach will be required, as described be- source function calculation techniques, two-dimensional
low. isodose curves’ or three-dimensional dose-rate curves10
were generated showing marked dose heterogeneity in
C. Pharmacokinetics modeling most tumor systems examined. Further studies remain to
be performed to be able to relate the dose-rate distributions
Pharmacokinetics modeling involves an attempt to esti-
to time averaged dose distributions, cell kill, and eventually
mate the biokinetics of tumor and normal organ uptake of
to therapeutic efficacy.
radiolabeled MoAbs on both a macroscopic and micro-
scopic level, and then to perform the dosimetric calcula-
tions. It is an essential component for estimation of cumu- G. Experimental RIT
lated activities in the various source regions of the body.
Radiolabeled MoAbs have been used for RIT of sphe-
Research is still required to find accurate and predictive
roids and a variety of murine syngeneic tumors and human
models of both macroscopic and microscopic pharmaco-
tumor xenografts. The results are summarized in the paper
kinetics. This subject is reviewed by Strand et al.5
by Buchsbaum et al. in this report.” The approaches taken
to estimate tumor dosimetry in the experimental animal
D. Calculation techniques for RIT studies include the MIRD approach, thermoluminescent
dosimetry, autoradiography, and comparison to external
Leichner and Kwok6 in this report provide a critical
beam irradiation. The uniform geometry of the spheroid
analysis of the calculational approaches that have been
has facilitated the estimation of radiation dose. The two
used for beta particle tumor dosimetry in RIT. In modeling
most important factors for therapeutic efficacy in the
of absorbed dose distributions, analytical, numerical, and
spheroid model are good penetration of the radiolabeled
Monte Carlo methods have been used to investigate the
MoAb and an adequate half-life of the radionuclide to ex-
effects of uniform and nonuniform activity distributions
ceed the time of penetration. The results in animal studies
associated with RIT.
indicate that MoAbs radiolabeled with a variety of radio-
nuclides have been effective in inhibiting tumor growth or
E. Microdosimetry
producing cures against a variety of tumor types. The ma-
Alpha emitters and internalized Auger electron emitters jority of investigators have estimated the dose to tumor
may be useful in RIT because of their high LET and RBE. using the MIRD formalism. A few investigators have esti-
However, the methodology to calculate dosimetry for short mated the dose to tumor using TLDs and autoradiography.
range alpha emitters and internalized Auger emitters must The effectiveness of RIT depends on a variety of factors
consider energy deposition at the cellular and subcellular including antibody specificity, affinity and immunoreactiv-
level. Such a microdosimetric approach which analyzes the ity, tumor vascularity, and differential radiation sensitivity
Medical Physics, Vol. 20, No. 2. Pt. 2, Mar/Apr 1993
501 D. J. Buchsbaum and B. W. Wessels: Introduction: Radiolabeled antibody tumor dosimetry 501
of the various tumor types. It must be kept in mind that is a potential advantage in therapeutic ratio predicted for
there are limitations of spheroid and animal models in alpha particle radiation when bone marrow (high linear-
modeling what occurs in the clinical situation.11,12 quadratic alpha/beta ratio) is considered as the critical
organ. 17
H. Imaging techniques and treatment planning
Leichner et al. 13 in another section of this report have ACKNOWLEDGMENTS
reviewed the various imaging techniques that have been We thank Donell Berry for typing the manuscript. Sup-
used for RIT treatment planning. They discuss tumor and ported by NIH Grant CA44173 and the Elaine Snyder
normal organ volume computations from CT and MRI Cancer Research Award.
data, correlative image analysis, and treatment planning
for RIT. “Correspondence should be sent to: Donald J. Buchsbaum, Ph.D., De-
partment of Radiation Oncology, University of Alabama at Birming-
ham, 619 South 19th Street. Birmingham, AL 35233-6832.
I. Clinical studies with dosimetry
1J. A. Siegel, B. W. Wessels, E. E. Watson, M. G. Stabin. H. M. Vrie-
There have been a large number of clinical RIT studies sendorp, E. W. Bradley, C. C. Badger, A. B. Brill, C. S. Kwok, D. R.
Stickney, K. F. Eckerman. D. R. Fisher, D. J. Buchsbaum, and S. E.
that have included tumor dosimetry estimates. The ap-
Order, “Bone marrow dosimetry and toxicity for radioimmunother-
proaches that have been taken in lymphoma, solid tumors, apy,” Antib. Immunoconj. Radiopharm. 3, 213-233 (1990).
and intraperitoneal therapy are described in three manu- 2S. A. Leibel, S. E. Order, D. R. Fisher, J. R. Williams, and R. J.
scripts in this report.14-16 Morton, “Physics and biology of radiolabeled antibodies workshop,
sponsored by the Radiation Research Branch, National Cancer Insti-
Radiation dosimetry in B-cell lymphoma patients has
tute, Division of Cancer Treatment, February 12-13, 1987, Bethesda,
been done using the MIRD approach. Organ and tumor Maryland,” Antib. Immunoconj. Radiopharm. 1, 271-282 (1988).
radionuclide activity measurements have usually been done ‘L. F. Mausner and S. C. Srivastava, “Selection of radionuclides for
radioimmunotherapy,” Med. Phys. 20, 503-509 (1993).
with conjugate view planar scintillation camera imaging.14
4E. E. Watson, M. G. Stabin, and J. A. Siegel, “MIRD formulation,”
Organ and tumor volumes have been obtained by CT,
Med. Phys. 20, 511-514 (1993).
SPECT, or the published values of the MIRD committee. 5S.-E. Strand, P. Zanzonico, and T. K. Johnson, “Pharmacokinetic
The range of tumor absorbed dose estimates in five clinical modeling,” Med. Phys. 20, 515-527 (1993).
6P. K. Leichner and C. S. Kwok, “Tumor dosimetry in radioimmuno-
lymphoma studies is reported.14
therapy: Methods of calculation for beta particles,” Med. Phys. 20,
For solid tumors, the MIRD approach, planar imaging 529-534 (1993).
and tumor volumetrics have been performed in a similar 7J. L. Humm, J. C. Roeske, D. R. Fisher, and G. T. Y. Chen, “Micro-
manner as in lymphoma studies.15 There have been wide dosimetric concepts in radioimmunotherapy,” Med. Phys. 20, 535-541
(1993).
variations in estimated tumor doses in different studies,
8E. D. Yorke, L. E. Williams, A. J. Demidecki, D. B. Heidorn, P. L.
and no definite dose-response relationship has been ob- Roberson, and B. W. Wessels, “Multicellular dosimetry for beta-
served. The spatial resolution limits of planar or SPECT emitting radionuclides: Autoradiography, thermoluminescent dosime-
imaging devices prevents detection of the nonuniformity of try and three-dimensional dose calculations,” Med. Phys. 20, 543-550
(1993).
radiolabeled MoAb deposition, and thus permits only the
9M. H. Griffith, E. D. Yorke, B. W. Wessels, G. L. DeNardo, and W. P.
estimation of average dose to tumor. Neacy, “Direct dose confirmation of quantitative autoradiography with
Regional administration of radiolabeled MoAbs has micro-TLD measurements for radioimmunotherapy,” J. Nucl. Med.
29, 1795-1809 (1988).
been used in the peritoneum, the cerebral spinal fluid, the
10P. L. Roberson, D. J. Buchsbaum, D. B. Heidom, and R. K. Ten
pleural/pericardial cavity, and within cystic brain tumors.
Haken, “Three-dimensional tumor dosimetry for radioimmunotherapy
Roeske et al.16 have reviewed the methods and results that using serial autoradiography,” Int. J. Radiat. Oncol. Biol. Phys. 24,
have been used for intraperitoneal dosimetry. 329-334 (1992).
11D. J. Buchsbaum, V. K. Langmuir, and B. W. Wessels, “Experimental
radioimmunotherapy,” Med. Phys. 20, 551-567 ( 1993).
J. Radiobiology of RIT
12B. W. Wessels, “Current status of animal radioimmunotherapy,” Can-
cer Res. (Suppl.) 50, 970s-973s (1990).
Langmuir et al.17 elsewhere in this report reviewed the
13P. K. Leichner, K. F. Koral, R. J. Jaszczak, A. J. Green, G. T. Y.
information available on the radiobiology of low-dose- rate Chen, and J. C. Roeske, “An overview of imaging techniques and
external beam irradiation and RIT as applied to tumor physical aspects of treatment planning in radioimmunotherapy,” Med.
dosimetry, and have discussed comparisons between the Phys. 20, 569-577 (1993).
14J. A. Siegel, D. M. Goldenberg, and C. C. Badger, “Radioimmuno-
two. Langmuir et al. 17 have concluded that tumors most
therapy dose estimation in patients with B-cell lymphoma,” Med. Phys.
likely to respond to RIT would be those types that are 20, 579-582 (1993).
inherently radiosensitive, those with a poor capacity to re- 15R. F. Meredith, T. K. Johnson, G. Plott, D. J. Macey, R. L. Vessella,
pair radiation damage or with long repair half-times, those L. A. Wilson, H. B. Breitz, and L. E. Williams, “Dosimetry of solid
tumors,” Med. Phys. 20, 583-592 (1993).
tumors that are susceptible to blockade in sensitive phases
16J. C. Roeske, G. T. Y. Chen, M. Reese, and A. B. Brill, “Dosimetry of
of the cell cycle, and tumors that reoxygenate rapidly. intraperitoncally administered radiolabeled antibodies,” Med. Phys. 20,
A comparison of alpha and beta emitters for RIT indi- 593-600 (1993).
cates an advantage for beta emitters if the linear-quadratic 17V. K. Langmuir, J. F. Fowler, S. J. Knox, B. W. Wessels, R. M.
Sutherland, and J. Y. C. Wong, “Radiobiology and radiolabeled anti-
alpha/beta ratio for tumors is greater than that of the crit-
body therapy as applied to tumor dosimetry,” Med. Phys. 20, 601-610
ical organ of toxicity, as is the usual case. However, there (1993).
Medical Physics, Vol. 20, No. 2, Pt. 2, Mar/Apr 1993
Selection of radionuclides for radioimmunotherapy
Leonard F. Mausner and Suresh C. Srivastava
Medical Department, Brookhaven National Laboratory, Upton. New York I I973
(Received 18 March 1992; accepted 6 October 1992)
I. INTRODUCTION sion electrons has been demonstrated.4-8 This effect can
best be realized with intranuclear localization of the radi-
The potential of utilizing monoclonal antibodies (MoAb)
onuclide, which does not generally occur with radiolabeled
as carriers of radionuclides for the selective destruction of
MoAb. Of course, a particles have a high linear energy
tumors (radioimmunotherapy, RIT) has stimulated much
transfer (LET) effective in cell killing and a range of sev-
research activity. The approach should be specially bene-
ficial for treatment of tumors not easily amenable to sur- eral cell diameters, 40-80 µm. The short ranges will accen-
gical control, for treatment of early recurrence and of dis- tuate inhomogeneous absorbed dose particularly when the
tant metastases. However, from dosimetric and other MoAb deposition is inhomogeneous. Beta particles are less
considerations, the choice of radiolabel is an important densely ionizing and have a range longer than a’s so that
factor that needs to be optimized for maximum effective- the distribution requirements are less restrictive for RIT of
ness of RIT. Most therapeutic trials to date have utilized bulky disease. On the other hand, for micrometastases, the
131I, largely due to its ready availability at moderate cost, absorbed fraction for higher energy beta particles (range
the ease of halogenation techniques for proteins, and its > tumor size) is decreased, leading to a less favorable tu-
long history of use in treating thyroid malignancy, rather mor absorbed dose. The gamma-ray energies and abun-
than any careful analysis of its suitability for RIT. This dances are also important physical properties, because the
paper briefly reviews the present and future radionuclides presence of gamma rays offers the possibility of external
that are considered particularly suitable for RIT. imaging but also adds to the whole body dose. These phys-
ical properties alone can be used to calculate radiation ab-
II. SELECTION CRITERIA sorbed dose at the cellular level. This approach has been
used by Jungerman et al.9 to estimate delivered doses for
The selection criteria must be based on the physical data
RIT. An approach which explicitly includes biodistribu-
about the radionuclide, its production and chemistry and
tion and kinetic data by using an idealized time-dependent
the biological variables governing its use. The important
averaged target-to-nontarget uptake ratio is that of Wessels
physical variables to consider include the radionuclide
and Rogus.10 Although the quantitative dose ratios are
half-life, the type, energy, and branching ratio of particu-
highly dependent on the input biodistribution data, a com-
late radiation and the gamma-ray energies and abun-
parison of the relative effectiveness of the radiolabels was
dances. It is important to match the physical half-life with
demonstrated. This relative efficacy was approximately
the antibody in vivo pharmacokinetics. If the half-life is too
constant for reasonable variation of model parameters in
short, most decay will have occurred before the MoAb has
accordance with observed biological data. A similar ap-
reached maximum tumor/background ratio.
proach was used recently by Yorke et al.11 Also, Humm12
Conversely, considerations of tumor radiobiology and
has considered the effect on MoAb dosimetry of varying
low radionuclide/antibody specific activity may also limit
tumor size and of cold regions. These papers underscore
the use of long-lived radionuclides. For equal radioactivity
the importance for therapy of a high ratio of nonpenetrat-
concentrations in the target, radionuclides with long half
ing to penetrating (g) radiations. The complex relation-
lives will produce a lower absorbed dose rate than those
with short lifetimes. If the maximum absorbed dose rate ship between tumor curability with different radionuclides
from beta particles is much lower than that typical in and tumor size has been reviewed by Wheldon and
brachytherapy (40-64 cGy/h), cell kill per cGy is O’Donoghue.13
decreased.1,2 The theoretical low specific activity of longer The main chemical variables to be considered in choos-
lived radionuclides would thus require a large mass of ra- ing a radionuclide for therapy with monoclonal antibodies
dionuclide, ligand, and antibody to achieve adequate dose are the radionuclide specific activity achievable, metal-ion
rate. This can make the use of long-lived radiolabels less contamination, the number of labels per MoAb molecule
desirable. However, if a two or three-stage therapy ap- obtainable without loss of immunological activity, and the
proach is utilized,3 it becomes useful to consider the use of stability of the radionuclide-protein attachment. The spe-
long-lived beta emitters, e.g., 32P and others. To some ex- cific activity, or amount of activity per mass of the element
tent the problem of low target dose rate may be counter- in question (MBq/mg), depends primarily on the method
acted by a number of factors including high nonpenetrat- of production. Simple neutron absorption reactions (e.g.,
ing equilibrium dose constant, high target to nontarget n ,)g generally give low specific activity since the radionu-
ratio, high carrier labeling efficiency, and the ability to clide cannot be chemically separated from a target of the
administer a large protein mass (tumor saturation effect). same element. Accelerator-based proton, deuteron, or
The type of particulate emission also must be consid- alpha-induced reactions are intrinsically no-carrier-added
ered. The potent lethality of Auger and low-energy conver- (NCA) methods that do allow chemical separation of
503 Med. Phys. 20 (2). Pt. 2, Mar/Apr 1993 0094-2405/93/020503-08$01.20 © 1993 Am. Assoc. Phys. Med. 503
504 L F. Mausner and S. C. Srivastava: Radionuclides for radioimmunotherapy 504
product from the target. This can also be achieved at re- ation is changing for several other attractive radionuclides
actors by neutron absorption reactions leading to an inter- to be discussed below.
mediate product with a beta decay to the desired final These physical and chemical factors must then be
product, or by fast neutron reactions such as (n,p). The viewed in light of available biological information. There is
achievable specific activity of these NCA methods then substantial variation in antibody uptake, macro- and
largely depends on the impurity levels of the product ele- micro-distribution, kinetics and processing (metabolism/
ment in the target or in various reagents used in processing. catabolism) depending on the particular antibody, anti-
An often overlooked source of carrier is due to the direct body dose, the variability of antigenic expression in the
production of stable isotopes of the product element. Al- tumor, its size and stage, etc. Limitations due to normal
tissue radiotoxicity are not entirely the function of radio-
though this effect is often negligible compared to carrier
nuclide emissions but are largely governed by the pharma-
introduced with the target, it can become significant with
cokinetics of the antibody. For many of the MoAbs and
very pure targets and high bombarding energies. With in-
MoAb fragments currently being investigated for immuno-
creasing energy, the typical peaks in nuclear excitation
therapy some generalities emerge. It is generally believed
functions broaden, usually reaching a plateau at approxi-
that one-half to three days is usually required to reach
mately 150-200 MeV and reaction cross sections for neigh-
maximum tumor uptake19-22 although optimum contrast
boring isotopes become comparable over large energy
with whole MoAbs may take longer. Despite the presence
ranges. Some of these issues have been reviewed recently
of numerous antigen sites on cancer cells, evidence from
for therapeutic radionuclides.14
tumor implanted microthermoluminescent dosimeter
The presence of metal ions other than the product is a
probes23,24 and autoradiography25 indicates a nonuniform
concern as they can compete for binding sites on chelate-
cellular distribution of the MoAb in most cases. This may
MoAb conjugates. It is largely controlled by the selectivity
be due to cell type heterogeneity,26 heterogeneity of anti-
of the chemical separation scheme, but this process is not
genic expression,27 poor delivery, and spatial inaccessibil-
perfect. For example, a normally adequate separation fac-
ity. These factors considerably reduce the attractiveness of
tor of 10-7 on a 10 g target still leaves 1 µg of target in the
short-ranged alpha-emitting radionuclides for radioimmu-
product which may be of concern when labeling at low
notherapy. A role for alpha emitters may be feasible in
protein concentrations. Indeed, measurement of these sta-
specific cases such as for micrometastases or intracavitary
ble species at low concentration in radioactive solutions is
administration for some types of cancers, such as perito-
often a very difficult practical problem. Although various
neal injection for ovarian carcinoma.28,29 The longer range
analytical procedures exist for detecting ions at subpart per
of beta particles can still permit uniform tumor irradiation
million levels, for example atomic absorption, emission
despite a marked heterogeneity of distribution of radioac-
spectroscopy, and x-ray fluorescence, these techniques of- tivity within the tumor. It appears desirable to deliver ion-
ten take time, utilize expensive instrumentation, and may izing radiation with a range of one to several millimeters in
require a large fraction of the final product solution for the tissue, as from intermediate to high-energy beta particles.
measurement. Generally, the sooner the radionuclide is
used the better, because its specific activity is highest, and Ill. CANDIDATE RADIONUCLIDES
this need competes with the desire to measure the specific
Relatively few alpha emitting radionuclides have been
activity and the impurity levels. Also, it is typical for many
considered for RIT. Bismuth-212 (t = 60.5 min, E = 7.8
research groups that the expensive analytical apparatus is 1/2 a
MeV) and 211At (t = 7.2 h, E = 6.8 MeV) are the two
not wholly owned. Instead, access is through a shared-use 1/2 a
nuclides that have been most studied.30-36 The 212Bi can be
facility whose operators are very reluctant to introduce
available via a 224Ra generator system,37 while 211At is ac-
radioactive material into their equipment. Thus the fastest,
celerator produced.38,39 The short half-life of 212Bi is not
albeit indirect method, of determining carrier levels may
well matched to MoAb uptake kinetics but it might be
simply be by titration with chelate during labeling.
possible to conjugate its parent 212Pb, with a 10.6 h half-
The convenience, efficiency, and gentleness of various
life, to a MoAb or MoAb fragment and thus generate the
radiolabeling procedures as well as the stability of the ra-
alpha emitter in vivo. The feasibility of this approach is
dionuclide attachment to the antibody are all very impor- under investigation.40 Nevertheless, the peak of 212Bi
tant factors which are being actively investigated by many
growth occurs at 3.8 h which is probably still too short for
groups. They will not be considered further here as these the peak in tumor uptake. The short life time of 211At and
topics are beyond the scope of this paper and have been limited availability may impede its use except in very spe-
reviewed several times.15-18 While recognizing the difficul- cial situations.41
ties in designing new conjugation schemes, at this point, it It has been suggested28 that the 20.1 h half-life of 255Fm
is simply assumed that adequate radiolabeling techniques is more appropriate for RIT. Unfortunately this nuclide
either exist or will become available for use with radionu- and similar alpha emitting heavy radionuclides (atomic
clides to be discussed.18 However, another practical aspect number > 82) are the parents or members of long decay
to be considered is that of radionuclide production-the chains involving both alpha and beta emission. Because the
routine availability, at reasonable cost, of quantities of ra- nuclear recoil from the alpha (and some of the beta) de-
dioactivity suitable for therapy. At present, only 131I truly cays are considerably more energetic than chemical bond
meets all of these production criteria. However, this situ- strengths, these transitions are capable of rupturing the
Medical Physics, Vol. 20, No. 2, Pt. 2, Mar/Apr 1993