NCI Radiation Research
Program Meeting Report
Clinical Research in Neutron Capture Therapy*
Running Title: Neutron Capture Therapy
by The National Cancer Institute Radiation Research
Program
Radiation Oncology Sciences Program
Radiation Research Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
EPN-6000
Bethesda, MD 20892-7440
United States of America
(301)
469-6111 voice
(301) 480-5785 fax
corresponding author:
rc148m@nih.gov (Richard L. Cumberlin)
Article Outline
*International
Journal of Radiation Oncology*Biology*Physics
A one and one-half day workshop to assess the current
state of the science in neutron capture therapy (NCT) was convened at the
request of the Radiation Research Program, Division of Cancer Treatment and
Diagnosis, NCI, and the U.S. Department of Energy. The topics were primarily
clinical with physics, chemistry, and biology relevant to immediate trials
discussed. The morning of the first day was directed to updates on epithermal
neutron sources, chemistry of medicinal boron compounds, and preclinical
studies. In the afternoon, participants from Europe, Asia, and North America
were invited to present their clinical experience with NCT. The participants
then separated into breakout sessions. The following morning session included
presentation and discussion each breakout session. These are presented below.
Appendix I includes the Workshop participants.
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Background
Neutron capture therapy was first proposed by in
1936, just four years after the neutron itself was discovered. NCT is a unique
form of radiation therapy that carries a potential for a significant
improvement in therapeutic gain. The classification of neutrons into energy
categories is somewhat arbitrary, but for the present purpose they mean:
"thermal neutrons" have an energy less than 1 ev, "epithermal neutrons" have an
energy between 1 eV and 10 KeV, and "fast neutrons" may be considered, for
therapy purposes, to be in the megavoltage range. NCT is a form of binary
therapy, similar to photodynamic therapy, in which neither the thermal neutrons
nor the boron carrier molecule has significant cytotoxic effect but produces
highly radiobiologically effective particles when the two interact. This is in
contrast to the more familiar "fast neutrons" which are highly
radiobiologically effective by themselves. These reactions between a neutron
carrier molecule such as boron-10 (B-10) and thermal neutrons produce He-4 and
Li-7 ions of very high LET but very short ( 10 microns) range. This therapy was first studied
in glioblastoma in 1951 using crude thermal neutron beams and B-10 enriched
boric acid. Since then, NCT has been studied in several countries and usually
with glioblastoma. The difficulties with NCT were, and continue to be,
difficulty in finding appropriate neutron beams, a scarcity of suitable boron
carrier agents, uncertain dosimetry, and lack of rigorous and reproducible
clinical trials. This workshop was convened to address these issues. These
issues were divided into three broad topics: carrier agent development,
preclinical studies, and clinical studies.
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Boron Agent Development
Design Requirements
Boron and carbon are the only two elements that are
capable of generating effective families of chemical compounds by bonding with
themselves or each other. Organoborane chemistry, however, is subject to unique
rules governing chemical structure and reactivity. These rules must be applied
to agent design and synthesis. Consequently, the design and synthesis of boron
agents for NCT differs significantly from the very active field of drug
discovery based upon classical organic chemistry. Operational differences
between boron agent design and conventional pharmaceutical discovery include
the absence of sufficient biological and structural data with which to approach
the computational design of boron agents. In addition, boron agent design,
synthesis and evaluation, by it's very nature, cannot be adapted to the
combinatorial synthesis methods which drive many of today's pharmaceutical
discovery programs. This is not to say that computational design methods cannot
be employed in the future as more stereoelectronic parameters are defined for
boron-rich structural groups.
The most important, but often overlooked, difference
between boron agents and conventional pharmaceuticals is the relative
therapeutic concentrations of the two types of compounds and the resulting
limitations that this places upon the use of molecular targeting with boron
agents. Therapeutic doses of boron-10 in tumor cells generally require 3-30
µg/gm of boron in tumor tissue or 109 atoms per cell.
Traditional pharmaceuticals normally function at concentrations orders of
magnitude lower than this. Put another way, traditional pharmaceuticals are
typically administered in the milligram dose range, whereas most current boron
agents are administered in the gram range, i.e., about a 1000-fold more of the
boron agent is required to reach a therapeutic concentration.
Boron agents and their attendant delivery features
may be classified on the bases of target recognition mechanisms and agent size.
Thus, four targeting categories are apparent: (1) global agents with no
targeting (2) agents that recognize malignant cells (3) agents that bind to
nuclei of cycling malignant cells, and (4) agents that both recognize malignant
cells and which bind to their nucleus.
Global, or category 1, agents have no targeting
features, low toxicity, low persistence and if present in very high systemic
concentrations (100-300 µg/gm boron) must be maintained by constant
infusion. Global agents are small, hydrophilic and incapable of crossing
protective CNS membranes.
Category 2 agents generally target receptors present
in the cell's plasma membrane followed by translocation into the cell or by
other processes which provide internalization such as passive diffusion,
transport proteins, metabolic processes and tumor specific membrane charges.
Low molecular weight agents of this type are represented by the boronated
porphyrin derivatives and boron-containing amino acids. High molecular weight
agents in this category include boron rich conjugated immunoproteins. Category
2 nanoparticulate agents are represented by boron containing unilamellar
liposomes and carborane-loaded low-density lipoproteins (LDLs).
Agents found in category 3 are useful only if they
accumulate in cells and have ample access to cell nuclei. Such agents are
represented by low molecular weight boron-containing nucleosides and
nucleotides. An example of cell incorporation for these agents is provided by
the hyperactivity of malignant cells and the rapid utilization of the nucleic
acid precursors in DNA synthesis.
Agents of category 4 are highly valued for their dual
ability to select tumor cells and localize to the tumor cell nucleus. Specific
cell-targeting may be provided to low molecular weight agents which enter the
cell nucleus and bind to DNA. This can be achieved, in principle, by
encapsulation of the agent in a tumor-targeting unilamellar liposome (ULL), or
by attaching a cell-recognition ligand, such as folate, to the agent. Thus
those Category 3 agents which have no organelle specific recognition properties
may be upgraded to category 4 by the addition of a specific delivery system.
Low molecular weight agents which fall into this group are represented by
acridines, phenanthridines, polyamines and oligomeric phosphate diesters
(OPDs). Evidence suggests that OPDs may have the ability to selectively target
tumor cells and translocate to the cell nucleus in therapeutic quantities
without additional cell-targeting modifications.
Of growing importance in boron agent design is the
recognition of nanoparticles (1-100 nrn diameter entities), such as unilamellar
liposomes (ULLs), unimolecular micelles (OPDs) and low-density lipoproteins
(LDLs) as boron-rich delivery vehicles directed to cellular receptor sites
which are hyperactive and over-expressed by malignant cells. Immaturity of the
vasculature and the resulting looseness of endothelial cell joining
characteristic of rapidly expanding tumor structures allows nanoparticulates to
leak into the intercellular volume through capillaries unique to the tumor
site. The use of small ULLs (<100 nm diameter) for the selective delivery of
boron agents to the interior of malignant cells has been extensively developed
and long-circulating so-called "stealth" liposomes and liposomes carrying
external immunoprotein attachments would be possible variants. Boron containing
nucleosides and nucleotides may also be encapsulated in ULLs and preferentially
delivered to tumor cells. Other species which may be useful for ULL
encapsulation are boron-rich DNA intercalators (acridine dyes and
phenanthridium cations), groove binders (bibenzimidazoles, netropsin and
distamycin), poly amines (spermidine and spermine) and di- and oligonucleotides
capable of antisense hybridization with DNA.
Small apoprotein-mediated LDL nanoparticles (<20
nm in diameter) become possible boron agent carriers following their isolation
from the patient and replacement of their cholesterol package with a
hydrophobic carborane derivative. The resulting very boron-rich LDLs are, in
principle, targeted to their original receptor sites by the presence of their
apoprotein marker. Thus, reinjection of the patient with viable boron-laden
LDLs should selectively deliver the agent to tumor cells which over express LDL
receptors.
Very small unimolecular micelles (<10 nm in
diameter) may offer an additional approach to nanoparticle delivery of boron to
malignant cells and at the same time increase solid tumor penetration due to
their small size. While little is known with regard to boron agent delivery by
micelles of any type, very small amphiphilic species represented by polyanionic
oligmoeric phosphate diesters (20-30% boron) appear to be effective. Very low
injected doses of OPDs in tumor bearing mice gave time-course biodistributions
which closely resembled those of ULLs many times their size. Other experiments
demonstrated translocation of OPDs from extracellular buffer to the cell
nucleus.
Recent modeling of lethality as a function of
subcellular boron distribution indicates that absolute boron concentrations of
20-30 µg/gm confined to the nucleus and/or the cytoplasm will assure cell
death under normal irradiation conditions. Since the nucleus of a cell may
constitute only 10-20% of its total mass, an analytical boron content, obtained
from tumor tissue analysis, of only 3 µg/gm would represent an absolute
boron content of up to 30 µg/gm (3 µg/gm x cell mass/nuclear mass)
if boron was largely confined to the nucleus. A lethal absolute boron content
of 30 µg/gm in cytoplasm would correspond to an analytical tissue
analysis of about 25 µg/gm boron. Thus, in the absence of subcellular
biodistribution data many agents investigated in the past which performed
poorly (say 5 µg/gm) on the basis of the accepted 30 µg/gm tumor
boron criterion, or were limited to a low boron value by systemic toxicity
issues, were discarded. If the analytical boron content of these cells was
actually localized in the nucleus or other critical organelle, the performance
of the agent could be quite useful if it were judged on the basis of its likely
performance in actual neutron irradiation experiments with the boron-10
enriched agent. Consequently, a low analytical boron content in gross tissue
analyses cannot necessarily be used to eliminate otherwise promising agents
from further consideration. A test based upon the radiobiological response of
the new boron agents might be more appropriate. Specifically, if the
radiobiological studies show that cell killing is much greater than would be
expected from the analytical boron content, this would provide a very good
indicator of intracellular localization whether accomplished in vivo or in
vitro. Knowledge of subcellular boron distribution is essential to
understanding the relationship of agent performance and should become a major
research focus.
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Agent Production Requirements
The production of boron target agents spans a range
of requirements which include the type of agent, quantity, purity and the
extent of boron-10 enrichment. All agents which enter clinical trials must be
boron-10 enriched (>95%) and manufactured in accord with FDA-approved GMP
procedures. The quantity of an agent required at any time is dependent upon
where the agent is located in its development cycle. Initial evaluation only
requires gram quantities, depending upon the agent's boron content. Advanced
evaluation in large animals could require less than a kilogram while clinical
trials would require several kilograms of boron-10 enriched GMP product.
Two important features of agent synthesis must be
emphasized. First, regardless of the detailed synthesis sequence employed,
agent syntheses rest upon the availability of boron-10 enriched inorganic
precursors which must eventually be available in large quantities of GMP
purity. All of these precursors are ultimately derived from boron-10 enriched
boric acid which is commercially available. Small commercial production
facilities exist for the synthesis of sodium borocaptate (BSH),
boronophrnylalanine (BPA) and GB10, which are agents involved, or soon to be
involved, in clinical trials. The second important feature regarding agent
synthesis is the fact that the chemicals, chemical reactions, compound
characterization, criteria of purity and purification procedures are unique to
polyhedral organoborane chemistry. While in many respects this chemistry
resembles and very often makes use of organic synthesis procedures, the
reactions involved in organoborane syntheses often have no counterpart in
organic chemistry and additional safety difficulties (fire and chemical
toxicity) may arise without the proper training of personnel. These are
surmountable problems, but they speak to the fact that dedicated facilities and
specially trained personnel are required to assure success.
The NIH Rapid Access to Intervention Development
(RAID) program is relatively new and effective in the proper context. Among the
RAID program functions is the synthesis of pharmaceuticals or their precursors
which allow an academic synthesis and evaluation program to go forward rather
than falter for lack of support at a critical moment. This program would be
ideal to assist in the synthesis or evaluation of a new agent. However, the
boron-10 enriched precursors, manufactured under GMP, are not commercially
available and any synthesis work undertaken under RAID auspices would require
beginning with boron-10 enriched boric acid and proceeding under GMP to the
product. As pointed out above, this is not organic chemistry and the work
involved is unique in the pharmaceutical field. The same situation arises in
the possible evaluation of agents using RAID expertise since the performance
milestones for boron target agents are quite different from those of
traditional pharmaceuticals. The boron agent development community could make
use of RAID if the necessity arose and cost effectiveness were evident.
Each research group pursuing the validation of new
agents cannot independently devote resources to the synthesis of boron-10
enriched decaborane from enriched boric acid solely to fulfill its own needs.
Since this is a relatively efficient task in the hands of experienced
personnel, it follows that all synthesis-oriented research groups (including
appropriate RAID projects) may benefit from the establishment of a medium scale
GMP synthesis facility. A facility of this sort could provide moderately priced
agents and agent precursors by building a stockpile of GMP boron-10 enriched
reagents for general use. At present, no such facility exists.
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Preclinical Studies
Animal Tumor Models
Animal tumor models provide the means for the
evaluation of boron compound biodistribution. Some NCT experiments can provide
information about the degree of tumor cell kill, which may be an indirect
measure of the boron distribution at the cellular level. Analytical techniques
do exist that can detect boron in individual cells, for instance secondary-ion
mass spectroscopy (SIMS). It is critical that animal experiments are carried
out with tumor models that mimic the relevant properties of human tumors, and
be coupled with analytical techniques of sufficient sensitivity to determine
biodistribution.
The particular boron compound may influence the
choice of an animal tumor if there is a biochemical basis for tumor
selectivity. For example, a boronated melanin precursor analog would be
screened in melanoma. Therefore because of the critical dependence of NCT
effectiveness on the delivery of the compound, a bank of tumor models that
differ in vascular density or in vascular supply would be very useful.
Subcutaneous tumors are generally considered adequate for in vivo screening,
whereas an orthotopic tumor model may be better for testing therapeutic gain
under neutron irradiation conditions. The standard endpoints used in animal
tumor model radiobiology such as tumor re-growth delay or cure probability are
perfectly adequate for NCT investigations.
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Normal Tissue Studies
In NCT radiobiology, measured biological
effectiveness factors for the component of the dose are a combination of the
intrinsic RBE of the high LET ions and the biodistribution of the particular
boron compound. This combined effect has been termed compound biological
effectiveness (CBE) factor. The calculation of the dose delivered to normal
tissues in NCT requires estimates of three basic parameters: (1) the boron
concentration (2) the CBE factors for that particular boron compound in the
tumor and in all normal tissues within the treatment field, and (3) the RBE of
the beam itself for the tumor and for the normal tissues involved (which
depends on accurate beam dosimetry). Animal models play an important role in
providing information on all three of these parameters.
Because the low energy thermal or epithermal neutron
beams cannot be easily focused or collimated, irradiated volumes are large.
Thus normal tissue response may be more of an issue with NCT than with
conventional photon therapy. As with conventional photon irradiation, normal
tissue response in NCT is related to the particular tumor site being addressed.
Animal irradiations for normal tissue response studies must be as close as
possible to the clinical situation under consideration . The normal tissues in
the treatment field will depend on the tumor site, but normal tissue response
studies in animals have been done, and clinical data exists for most of the
tissues involved (e.g., skin, brain, the lung, oral mucosa). Much of this
normal tissue response work has been carried out in rats. If NCT is ever
applied to the treatment of prostate carcinoma, the critical normal tissue
involved, the rectum, would require a larger animal model such as the dog.
Because NCT radiobiology requires the experimental
generation of correction factors for biological effectiveness in order to
account for the high-LET beam components, animal model systems used for these
studies should have easily measured endpoints. For example, in the CNS, the rat
spinal cord model is used extensively. The endpoint is paralysis within seven
months. Paralysis is a quantal response and the data can be fitted by logit or
probit analysis and the LD50 with confidence limits can be determined.
Comparison of the LD50 for a photon reference irradiation, the thermal neutron
beam only, and the thermal neutron beam in the presence of boron compound
allows the estimating of RBEs for the effects of the thermal beam and the
specific CBE factors for the particular boron compound. However, paralysis is
not the endpoint expected in the human clinical trials with brain tumors. A
functional assay of CNS damage would be more appropriate. MRI changes are an
indication of subclinical damage. Though clearly more relevant to the clinical
situation, these endpoints are more difficult to quantify. Patients in the NCT
clinical trials have exhibited a somnolence syndrome. There is no animal model
for a somnolence syndrome. This is a general problem for any treatment for
brain tumors where the anticipated adverse effects are cognitive in nature.
In the end, NCT radiobiology must always be viewed as
a model system that provides a guide to the estimate of NCT doses in the
clinical situation. NCT clinical trials will rely on dose escalation to
conservatively approach tolerance doses in humans. Validation of the calculated
photon-equivalent doses currently being used in NCT clinical trials can come
from animal models, where the effects of Gy-Eq doses delivered during boron
neutron capture irradiations can be compared with the known response of the
tissue to photon irradiation or from the NCT clinical response data, if there
are endpoints reached in the NCT dose escalation trials that can be related to
the known response to photons of the tissue in question.
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Dose-Volume Considerations
The recent initiation of clinical trials of NCT for
glioblastoma multiforme using epithermal neutron beams capable of penetration
through closed scalp and cranium, has required careful calculation of the dose
to the normal brain, including measurement of the biological effectiveness
factors for the high-LET components of the normal brain dose. Much of the work
on the response of the central nervous system to NCT has been done in the rat
spinal cord model using a thermal neutron beam. The epithermal beams required
for adequate neutron penetration in the human brain are inappropriate for use
in the rat. Epithermal neutrons require several centimeters of tissue, in which
little neutron capture reactions occur, to dissipate the energy necessary to
become the thermal neutrons needed for the neutron capture process. Also, in
the clinical situation, the normal brain dose decreases as a function of depth,
making volume a potentially critical parameter; a parameter that is difficult
to incorporate in studies using the rat spinal cord. To more closely
approximate the clinical situation, epithermal neutron beams have been used in
normal tissue response studies in the canine brain but primate models may be
necessary.
The lung is another site where dose volume
relationships are critical. There have been reports of Adult Respiratory
Distress Syndrome after NCT treatment to the brain. Whether this is due to
uncollimated scatter, head leakage, or other factors, it is known that partial
irradiation of the lung can trigger a more widespread pneumonitis reaction due
to the release of cytokines. If NCT is to be applied to lung tumors, or for the
analysis of the effects of the scattered dose to the lung from treatment of
head and neck tumors, small animal models may be sufficient for initial
studies, but larger animals such as the dog or the pig will be required for
definitive studies.
Analysis of the results of the NCT clinical trials
will involve dose-volume histograms (DVH). In this regard NCT dosimetry is
unusually complex. The DVH for each of the beam components is different. For
example, the DVH for the region of brain for the fast neutron component of the
dose will be different from the DVH for the region of brain for the gamma
component and likewise for the neutron capture components of the dose. This is
not an insurmountable problem, but must be remembered when doing these analysis
and will require accurate beam characterization and dosimetry.
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Evaluation of New Agents
Thorough evaluation of new compounds must provide
data on cytotoxicity, in vitro uptake of the agent by model cell lines, tumor
and blood analysis for boron concentration and, if possible, time-course
biodistribution. The increasing recognition of subcellular boron distribution
in model cells as an important parameter in agent evaluation and molecular
targeting has led to the development of new analytical procedures for this
purpose. Microdistribution of boron has been studied using a-track
autoradiography, electron spectroscopic imaging (ESI), electron energy loss
spectroscopy (EELS) and secondary ion mass spectroscopy (SIMS). These are not
routine measurements and they pertain to very few agent and cell types.
Analytical boron concentrations that may not appear to be high enough for
efficacy may be misleading if the observed boron were actually localized in the
nucleus or other critical organelle.
Care must be exercised in the use of in vitro agent
uptake by model cell lines since the most common method employed to monitor
such experiments has employed the quantification of cellular death upon
irradiation of boron-loaded cells with a thermal neutron source. False positive
results can and have been obtained in the past due to the presence of
non-specifically bound agents at the plasma membrane surface. This can normally
be prevented by thorough washing of the cell suspension before irradiation.
Other results obtained from in vitro experiments which employ nanoparticle
agents may be unreliable because nanoparticle uptake often requires long
periods to reach maximum values in vivo and the properties of the nanoparticles
may be significantly different in serum and buffer suspensions. However, the in
vivo evaluation of small molecules and nanoparticles using small animal models
overcomes the uncertainties mentioned above and provides a clear view of
competitive uptake by the reticuloendothelial system, blood clearance, tumor
accretion and systemic toxicity under conditions resembling those encountered
in humans. Thus, nanoparticle agents require evaluation in time-course
experiments carried out over an extended time. The minimal tissue requirements
for boron analysis in all time-course experiments are blood, liver, spleen,
tumor and relevant normal structures.
Low molecular weight agents would advance to small
animal evaluation, as described. If agents of any type displayed attractive
properties through small animal evaluation, the next steps would involve
biodistribution studies, systemic toxicity evaluation and dose escalation using
large animals such as dogs or monkeys. Following the collection of these data,
the large animals would then be subjected to neutron irradiation using boron-10
enriched agents. Sufficient large animal data would then be collected to move
the new agent into the clinical trial protocols.
It must be emphasized that there can be no strictly
uniform evaluation protocol for agents of all types created to serve all
varieties of tumor. Evaluation protocols must remain sufficiently flexible to
evaluate unusual agents. The tumor types of interest to the clinical community
must be defined to guide agent design and establish agent evaluation standards.
One or more centralized facilities for biological
evaluation may be helpful. Such a facility should be equipped with the proper
laboratory equipment and instrumentation, a vivarium (or equivalent) and both
thermal and epithermal neutron sources properly equipped for irradiation
experiments. Such a facility should be staffed with personnel having extensive
experience in the biological aspects of NCT. The centralization of biological
evaluation work would provide validation of the models, and uniformity of
biological standards, the capability to perform nonroutine evaluations, provide
a selection of well-maintained cell lines as well as neutron sources and the
means to accumulate a meaningful data base.
The no-cost ICP-AES boron analyses of tissue and
other research samples now provided by the Idaho Nuclear Engineering and
Environmental Laboratory (INEEL) under DOE auspices should be continued and
offered to the scientific community as a service. Data obtained by this means
has been invaluable for the determination of boron concentrations in
nonbiological as well as biological research samples not directly related to
biodistribution studies. This will not be sufficient for a thorough evaluation
which will also require support of ESI, EELS, and SIMS facilities to determine
boron microdistribution. Many compounds that are taken up in the cell, but are
sequestered away from the nucleus or other critical organelle could be quickly
eliminated from consideration if this were part of an initial evaluation
process.
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Clinical Studies
Neutron capture therapy was first investigated in
patients with malignant glioma from 1951 to 1962 at Brookhaven National
Laboratories and at MIT. These trials used non selective boric acid derivatives
and inadequate thermal neutron sources. The Japanese began clinical trials in
1968 using the somewhat more tumor-selective compound BSH. The preponderance of
experimental and clinical work on NCT has been directed toward glioblastoma
multiforme, a tumor poorly responsive to any form of treatment. Phase I trials
in this disease have been initiated at Harvard-Massachusetts Institute of
Technology (Harvard-MIT), Brookhaven National Laboratory (BNL), The Netherlands
(European Consortium) and most recently Helsinki, Finland.
It is not necessary, nor even desirable, to confine
NCT trials to glioblastoma multiforme. Many tumor types have shown sufficient
uptake in order for NCT to be considered a possibility; among these are
non-small cell lung carcinoma, metastatic colon adenocarcinoma, malignant
melanoma, and anaplastic thyroid carcinoma. Before clinical trials can be
initiated, many factors in addition to tumor uptake of a boron-containing
compound need to be taken into consideration. It will be necessary to know the
uptake of adjacent and potentially dose-limiting normal tissue and the detailed
pharmacokinetics of boron in the tumor and irradiated normal tissue. Toxicity
needs to be assessed well outside of the treatment field because of the poor
colomnation of thermal neutron beams. Malignant melanoma is an especially
attractive disease for a proof-of-principal phase II study in that BPA was
developed specifically for melanoma and pharmacokinetic studies suggest a tumor
to blood boron concentration of 3-4 to 1, translating in principle into a
therapeutic gain of 1.4.
The availability of adequate sources of epithermal
neutrons is an impediment to clinical research with NCT. Right now, there is
only one available in the United States (MIT) and four others in Europe and
Japan. There are presently two trials with glioblastoma in the U.S. and two
others in Europe and Japan. One trial with melanoma and one with lung cancer
are also underway in the United States. The neutron sources used in these
trials are derived from nuclear reactors, each with its unique beam
characteristics. The epithermal neutron is not monoenergetic, and it also
contains high energy gamma radiation and fast neutrons, both of which damage
tumor and normal tissue unrelated to the presence of boron. This makes it
difficult to compare clinical results from different centers. If collaborative
clinical trials are to be done, it will be necessary to develop a consistent
procedure for dosimetry calculations and reporting, which may require that each
beam component be analyzed separately. A uniform method of beam
characterization with standardized phantoms will also be necessary. Such a
phantom has yet to be developed.
Effective BNCT need not be based upon the use of a
single agent. Multiagent therapy may overcome heterogeneity of tumor structure,
cell type and dose-limiting systemic toxicity in much the way that combination
chemotherapy has been shown to do. Agents effective against particular
subcellular compartments might be used in combination with one another, but at
lower individual doses, and in a complementary manner providing boron
throughout the complete cell while minimizing any systemic problems arising
from a particular agent. For example, cells in active DNA synthesis may
preferentially incorporate bornated nucleosides while cells in active protein
syntheses may show a preference for boronated amino acids. The timing of the
administration of these "cocktail" components could be such that they
simultaneously reach their maximum effectiveness at the time of neutron
irradiation. The possibilities for customizing a combination of agents for a
particular tumor type are attractive.
NCT has traditionally been given in a single
treatment, largely for logistical reasons. Conventional photon treatments and
fast neutron treatments are given in several fractions. It is unlikely that a
single administration of boron agent will incorporate in enough tumor cells for
optimal NCT. Several administrations may be necessary to assure uptake in the
remaining tumor cells. In addition, fractionation may minimize the effects of
the beam contaminants that damage normal tissue independent of boron. This is a
prime area for clinical research.
A related area is the use of concomitant fractionated
NCT boost, given with fast neutron irradiation. Thermal neutrons are produced
spontaneously in tissue from fast neutrons at depth. This has the advantage of
not requiring that every tumor cell take up boron since the fast neutrons are
lethal by themselves. Fast neutron beams also collimate better that epithermal
beams thus irradiating less normal tissue as the beam enters and exits the
patient. Pre clinical studies suggest that a dose enhancement factor of 1.3
relative to fast neutrons alone can be achieved. This area of research is in
the early stages and should be pursued.
Rather than localizing the epithermal neutrons, it
may be more helpful to localize the boron agent since without boron-10 in
normal tissue, the neutrons would have no toxicity and the effectiveness of
BNCT depends on having a sufficient concentration of boron in the tumor cells.
Intra-arterial administration of boron compound is one method of achieving
this, much as intra-arterial limb and hepatic perfusion is done with
chemotherapeutic agents. For glioma, this administration may be enhanced using
blood-brain barrier disruption with mannitol or similar agent. This has been
demonstrated in laboratory animals but has not yet been evaluated in the
clinic. Another promising method of boron delivery is to conjugate a suitable
boron compound with a ligand for a cell membrane receptor that is
preferentially overexpressed in malignant cells. This is similar to the use of
conjugating radioactive iodine to monoclonal antibodies for specific surface
receptors but would not have the systemic toxicity seen with radiosotopes. This
has been done in vivo with epidermal growth factor (EGF) targeting the
epidermal growth factor receptor (EGFR) which is known to be overexpressed in
several malignancies. This area of research is also in the very early stages
and should be pursued. Perhaps some combination of neutron localization and
boron localization may show substantially less toxicity and greater efficacy
than either localization method alone.
As mentioned, there are a limited number of neutron
sources worldwide modified for clinical use. More than a dozen research
reactors are located at universities and national laboratories near major
medical centers in the U.S. and are suitable for conversion to clinical use
provided there is sufficient justification for doing so. To this end, a
definitive proof-of-principle clinical trial is essential. In addition,
research groups at MIT, Lawrence Berkeley National Laboratory, Brookhaven
National Laboratory, and elsewhere are designing linear accelerators with
sufficient neutron intensity for NCT. Now, its greatest promise is in
locoregional disease that other therapies cannot effectively treat. This may
change considerably if agents can be developed that give a tumor to normal
tissue concentration of 10:1 or better. This may be possible with further
advances in molecular targeting technology. If NCT then proves to be successful
and comes to enjoy an applicability that exceeds the capacity of a handful of
reactor-based clinical units or fast neutron units, then hospital-based
accelerators designed specifically for NCT could be produced and put into
routine clinical use much like the accelerators in widespread use for photon
radiation therapy.
For the present, however, the difference between
encouraging well designed clinical trials with appropriate endpoints and
advocating NCT as a proven therapeutic alternative must be made clear..
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Appendix I. Workshop
Participants
Rolf F. Barth, MD, Ohio State University
James E.
Boggan, MD, UC Davis
Paul Busse, MD, PhD, Beth Israel Deconess Medical
Center
Jeffrey A. Coderre, PhD, Brookhaven National Laboratory
Aidnag
Z. Diaz, MD , Brookhaven National Laboratory
Reinhart A. Gahbauer, MD, Ohio
State University
Patrick R. Gavin, PhD, Washington State University
M.
Frederick Hawthorne, PhD, UCLA
Roger Henriksson, MD, Umea University
(Sweeden)
John W. Hopewell, PhD, Oxford
George Kabalka, PhD, University
of Tennessee
Stephen B. Kahl, PhD, UCSF
Merja Kallio, MD, PhD, Helsinki
University
Irving D. Kaplan, MD, Beth Israel Deconess Medical Center
Jody Kaplan, RN, BSN, Beth Israel Deconess Med Ctr.
Peter T. Kirchner,
MD, U.S. Department of Energy
George E. Laramore, MD, PhD, Univ of
Washington
Yoshinbu Nakagawa, MD, National Kagawa Children's Hospital
(Japan)
Matthew R. Palmer, PhD, Beth Israel Deconess Medical Center
Wolfgang Sauerwein, MD, PhD, Universitaetsklinik und Strahlenklinik
(Germany)
Raymond F. Schinazi, PhD, Emory University
Albert H. Soloway,
PhD, Ohio State University
Werner Tjarks, PhD, Ohio State University
Nora Volkow, MD, Brookhaven National Laboratory
Charles A. Wemple,
Ph.D, INEEL
Richard J. Wiersema, PhD, Neutron Therapies, LLC.
Robert G.
Zamenhoff, PhD, Harvard-MIT
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