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Journal of Neuro-Oncology 33: 9–18, 1997.  1997 Kluwer Academic Publishers. Printed in the Netherlands.

The rationale and requirements for the development of boron neutron capture therapy of brain tumors Albert H. Soloway, Rolf F. Barth, Reinhard A. Gahbauer, Thomas E. Blue and Joseph H. Goodman The Ohio State University, Columbus Ohio 43210, USA

Key words: boron neutron capture therapy, binary systems, glioblastoma multiforme, neutrons, boron compounds, therapy Summary The dismal clinical results in the treatment of glioblastoma multiforme despite aggressive surgery, conventional radiotherapy, and chemotherapy, either alone or in combination has led to the development of alternative therapeutic modalities. Among these is boron neutron capture therapy (BNCT). This binary system is based upon two key requirements: (1) the development and use of neutron beams from nuclear reactors or other sources with the capability for delivering high fluxes of thermal neutrons at depths sufficient to reach all tumor foci, and (2) the development and synthesis of boron compounds that can penetrate the normal bloodbrain barrier, selectively target neoplastic cells, and persist therein for suitable periods of time prior to irradiation. The earlier clinical failures with BNCT related directly to the lack of tissue penetration by neutron beams and to boron compounds that showed little specificity for and low retention by tumor cells, while attaining high concentrations in blood. Progress has been made both in neutron beam and compound development, but it remains to be determined whether these are sufficient to improve therapeutic outcomes by BNCT in comparison with current therapeutic regimens for the treatment of malignant gliomas.

Introduction The number of new, primary central nervous system (CNS) tumors in the United States for 1995 has been estimated at 17,200 and the number of deaths projected at 13,300 [1]. Among children who are younger than age 15, CNS tumors rank as the leading cause of death from solid tumors. Among adults, 18 are affected per 100,000 by age 70 [2]; and, for those over the age of 75, the annual rate of primary malignant brain tumors has increased 23.4%. Based upon these statistics and even without considering malignancies that are metastatic to the CNS, it is clear that brain tumors are an important public health problem in the United States, especially in light of the increased life expectancy in population.

Of all primary brain tumors, 65% are gliomas, most being anaplastic astrocytomas and glioblastoma multiforme (GBM). Although these tumors rarely metastasize to other sites and organs, they have a highly infiltrative growth pattern, penetrating into surrounding normal brain from a few centimeters even to the contralateral cerebral hemisphere. This growth pattern has made it virtually impossible to surgically resect glioblastomas in their entirety. Surgery is important for tumor debulking and in alleviating symptoms, but as the sole treatment modality, it is ultimately ineffective for GBM. The objective of any new treatment for GBM must be to eradicate residual tumor foci, which may have escaped surgical resection, without enhancing the morbidity and mortality normally associated

Please indicate author’s corrections in blue, setting errors in red 121161 NEON ART.NO 733AS (589) ORD.NO 234589.Z

10 with this malignancy. In effect, one must be able to destroy disseminated tumor cells, whose precise location is unknown, irrespective of whether or not they are hypoxic and/or protected by the normal intact blood-brain barrier (BBB). Additional complications stem from the marked heterogeneity of GBM cells, variability in their proliferative rates, and their differential sensitivity to a variety of cytotoxins, including radiation [3]. In addition, treating tumors of the CNS poses distinct problems in itself. As with all therapeutic modalities for treating cancer, normal tissue tolerance is the key limitation, with the hope being that normal cell regeneration will repair tissue damage associated with the treatment. However, in the CNS, for all practical purposes, the normal cells are not undergoing cell division; therefore, the loss of neurons cannot be compensated for by their repopulation. Also, the CNS and brain tumors possess cellular and membrane barriers that may significantly restrict penetration by a variety of drugs and other chemical compounds. In view of the fact that tumor cells may be disseminated throughout the brain at the time the patient first becomes symptomatic, it is essential that GBM be treated as a whole brain disease. Nonetheless, even when the malignancy recurs only at the initial disease site, the need for sterilizing all tumor cells remains the crucial requirement if any treatment modality is to be effective.

Radiotherapy Since surgery alone, even with wide margins of resection, typically fails to control the disease, it has been necessary to consider the use of combined treatment modalities. Of these, radiotherapy has been one of the more widely used in conjunction with surgery. External beam whole-brain radiation therapy at dosages of 50–60 Gy has proven to be effective in treating lower grade gliomas with a significant improvement in median survival over surgery alone. In GBM, the median survival is extended by an approximate factor of 2.5 over surgery alone, yet long term survival is rare [4]. This applies not only to the use of conventional dose fractionation schedules

with and without hypoxic cell sensitizers, but also to protocols with hyperfractionation [5] or brachytherapy [6] with and without hyperthermia utilizing a variety of different radionuclides, stereotactic interstitial radiosurgery [7, 8], 3D conformal X-ray therapy and external beams consisting of low or high linear energy transfer (LET) radiation. While low LET radiation was shown to improve median survival over surgery alone, tumor regrowth is the rule even at very high doses. In contrast, fast neutrons have consistently been shown to have some effectiveness in treating GBM, but the results on the tumor have been complicated by late normal tissue effects in terms of morbidity and survival. No therapeutic window was found for fast neutrons, and in a majority of autopsies performed, there was both tumor and normal tissue necrosis [9–12]. However, the results suggest that higher LET radiation, if confined to the tumor, may be highly beneficial. The radiation resistance of GBM cells has remained a significant impediment in the control of this tumor by radiation protocols. Although such tumor cells can be destroyed per se, especially by high LET radiation, the destructive effects in vivo unfortunately cannot be solely confined to the tumor. The radiation levels required for tumor control also deliver unacceptable doses to normal brain and vascular endothelial cells. However, the very fact that such tumor cells can be eradicated by high LET radiation means that, if a suitable dose differential between tumor and normal tissue could be attained so that normal tissue tolerance were not exceeded, then tumor control might be achieved.

Chemotherapy A second modality for combination with surgery involves the use of chemotherapeutic agents [13]. Such drugs have been shown to prolong the survival of patients with anaplastic gliomas, oligodendrogliomas, medulloblastomas, neuroectodermal tumors, primary central nervous system lymphomas, and germ cell tumors, but the cure rate has not increased significantly over surgery and radiation alone. The chemotherapeutic agents include various alkylating agents and prominent among these


11 are the nitrosoureas; antimetabolites, such as those related to pyrimidines, purines and folic acid analogues; antibiotics and alkaloids, some of which are topoisomerase inhibitors; and miscellaneous compounds, one category being the polyamine inhibitors. Unfortunately, among brain tumors, GBM appears to be resistant to these chemotherapeutic agents, even when they are used in combination with other therapeutic modalities. What contributes to the complication in the use of chemotherapeutic compounds for brain tumors is the restrictive nature of the normal BBB, which limits compound access to the brain and thereby to tumor cells protected by the normal BBB. In order to overcome this limitation and enhance tumor drug delivery while minimizing systemic toxicity, intra-arterial administration in combination with BBB disruption have been proposed [14]. Although systemic toxicity may be reduced and the concentration of drug reaching the tumor may be increased correspondingly, greater amounts are also delivered to normal brain, resulting in increased neurotoxic effects. Thus, GBM cells are resistant not only to radiation but to chemotherapeutic agents as well. Unless new agents are developed with the potential to selectively destroy tumor cells without concomitantly injuring normal brain, chemotherapy of brain tumors will continue to have serious limitations, especially for GBM.

volves using agents that produce a clear dose differential between tumor and normal tissue. The therapeutic challenge is to achieve this differential in spite of the problems discussed in the preceding sections. Boron neutron capture therapy Boron neutron capture therapy (BCNT) is one of the more complex forms of therapy, and for this reason it has taken significant time to develop since it was first proposed by Sweet and Javid for treating intracranial tumors [16]. BNCT is based upon the nuclear fission that occurs when nonradioactive 10B (comprising in nature approximately 20% of elemental boron) absorbs thermal or slow neutrons (0.025eV) and generates high LET particles. These particles consist largely of alpha particles and lithium nuclei, sharing between them 2.3–2.8MeV and having a range of 5–9 micrometers. Boron-10 is not

Figure 1. Nuclear reaction of boron-10 with thermal neutrons.

Innovative therapies It is precisely for this reason that innovative therapies for GBM have been undertaken [15]. These include brachytherapy, hyperthermia, immunotherapy, gene therapy and binary systems such as radiation sensitizers, photodynamic therapy, and BNCT. The theoretical advantage of such binary systems is the potential to deliver a cytotoxic agent to malignant cells while sparing contiguous normal brain. That is the objective. However, its success is dependent upon the ability to design and develop delivery agents with the capability of not only penetrating the BBB but selectively targeting malignant cells, even those that might be protected by the normal BBB. For radiation-related modalities, this in-

the only nuclide that has a high capture cross section for thermal neutrons. Table 1 lists a number of such nonradioactive elements and their thermal neutron capture cross section values expressed in barns (1 barn= 10−24 cm2). This is the effective cross section area that the nucleus presents for thermal neutron absorption. Although a number of these nuclides possess comparable or even higher cross section values than boron-10, the clear advantages of boron-10 are: (1) the particles emitted produce high LET radiation that is limited to a very short track length, no greater than the diameter of a single cell; and (2) boron compounds rival carbon in their extensive covalent chemistry and stability, allowing for the synthesis of many very different chemical entities, ranging from low molecular


12 Table 1. Non-radioactive elements with high thermal neutron capture cross-section values [17] Nuclide

6

Li B 113 Cd 149 Sm 151 Eu 155 Gd 10

Neutron capture Nuclide cross-section values*

157

942 3,838 19,800 42,000 5,800 61,000

Gd Dy 168 Yb 184 Os 196 Hg 199 Hg 164

the former produces gamma rays generated in the capture reaction and the latter produces protons.

Neutron capture cross-section values (σ)*

H + 1nth → [2H] → 2H + γ (2.23 MeV) N + 1nth → [15N] → 14C + 1p (0.63 MeV)

1

14

255,000 1,800 3,500 3,000 3,000 2,000

Furthermore, the loss of energy by neutrons in tissues occurs mainly by scattering with hydrogen, which creates energetic recoil protons as secondary particles that deposit radiation dose to tissue. Since the radiation dose from reaction with hydrogen and nitrogen is directly dependent upon the neutron fluence and occurs both in normal and malignant cells, it is essential that the boron concentration in the tumor be in the range of 20–40 micrograms per gram (109 10B atoms/cell) in which case z 75–80% of the radiation dose arises from the 10B fission reaction. Concomitantly, the boron differential between tumor and surrounding normal tissues in the path of the neutron beam should be as high as possible in order to ensure that normal tissue tolerance is not exceeded, while selectively destroying tumor cells. The ideal agent would achieve high intracellular concentration in the tumor and preferably be bound to or incorporated into tumor DNA, which is the ultimate target. In addition to the development of suitable compounds, which either intrinsically or by metabolic conversion can achieve the appropriate concentration in tumor cells, beams of neutrons are necessary that produce only few ionizing events in tissue themselves, yet produce large numbers after their capture by 10B. The only currently available neutron beams possessing such attributes are those produced by a nuclear reactor.

* Neutron cross section in (σ) barns (b= 10−24 cm2).

weight to macromolecular species. Attempts have been made to synthesize compounds, that are related to natural biochemical constituents. The rationale for their development is that malignant glioma cells during the S phase of the cell cycle may have a greater requirement for such intermediates than do normal glial cells, and, in this way, concentration differentials may be achieved between neoplasm and normal brain. The basis for BNCT stems from the fact that the nuclear capture cross section values of normal tissue elements for thermal neutrons (Table 2), are two orders of magnitude less than 10B in most cases, they are so low that they contribute little to the radiation dose after exposure to thermal neutrons. Based upon their percentage in tissue, their capture cross section values for thermal neutrons and the types of radiation emitted in their nuclear reactions, the two elements because of their widespread distribution in tissue that may contribute to the background radiation dose, are hydrogen and nitrogen;

Table 2. Thermal neutron capture cross-section values of elements and their percentages in tissue [17] Nuclide

Weight % in tissue

Neutron capture cross-section*

Nuclide

Weight % in tissue

Neutron capture cross-section*

H C N O Na Mg

10.0 18.0 3.0 65.0 0.11 0.04

0.332 0.0034 1.82 1.8 × 10−4 0.43 0.053

P S Cl K Ca Fe

1.16 0.20 0.16 0.20 2.01 0.01

0.18 0.53 32.68 2.1 0.4 2.57

* Neutron cross section (σ) in barns (b= 10−24 cm2).


13 From the foregoing, it should be apparent that in addition to the involvement of clinicians such as neurosurgeons and neuro- and radiation oncologists, it also is necessary to have nuclear engineers and physicists, synthetic chemists, biochemical pharmacologists, pharmacokineticists, and radiation biologists involved in the development of BNCT.

Initial clinical efforts and requirements for BNCT Early clinical failures in the development of BNCT [18, 19] stemmed not from flaws in the concept, but from the biological and biochemical inadequacy of the boron compounds available and the limitation of the existing neutron beams. The agents that were available lacked the necessary selectivity for malignant cells, including those that may be protected by the normal BBB. Furthermore, boron concentrations were higher in the blood than in the tumors. Consequently, severe injury to the vascular endothelium occurred and ultimately produced radiation necrosis [19]. The clinical consequence was expressed in most cases as a gradual deterioration in the status of the patient, simulating GBM recurrences. This prompted efforts to develop boron compounds that would possess more desirable biological properties, i.e., compounds that would show greater selectivity for tumor cells and especially lower blood concentrations than those in tumor. The two agents that are being used clinically in the United States and Japan are sodium mercaptoundecahydrododecaborate (Na2B12H11SH (BSH)) [20] and p-boronophenylalanine (BPA) [21]. Both were synthesized and evaluated more than 30 years ago. They have more desirable biological properties than the compounds used in the earlier clinical trials. However, the process by which they are metabolized and the biochemical basis for their accretion in tumors have not been determined. Nevertheless, clinical trials with BSH and BPA are in progress to assess their potential usefulness as capture agents for BNCT and to determine whether either of these agents meets the minimum requirements for BNCT.

Initially, the nuclear reactor-derived beams available were composed of thermal neutrons and lacked the ability to penetrate tissue and deliver suitable neutron fluxes to the tumor beyond 2–3 centimeters. Therefore, in these studies the scalp and cranium were reflected immediately prior to patient irradiation, to create a void space for the thermal neutrons allowing them to enter the brain directly at the site of tumor resection. This limitation in the penetration characteristics of thermal neutron beams is shown in Figure 2. As a result,

Figure 2. Depth dose reduction: thermal neutrons vs soft X-rays.

Fairchild proposed the use and development of epithermal beams [22]. Such beams have more energetic neutrons and are capable of penetrating to increasing depths while still retaining low potential for direct tissue damage by ionization. The approximate energy of neutrons with the minimum potential for ionization is 40eV, compared with 0.025eV for thermal neutrons. Their energy is reduced as they penetrate tissue, and these neutrons are thermalized, producing maximum thermal neutron fluxes at depths that are several centimeters below the surface. The development of these beams provides a more constant thermal neutron flux at increasing depths and appears to obviate the need to reflect scalp and bone flaps in BNCT irradiations (Figure 3). Intense monoenergetic 40eV beams currently are not attainable because nuclear reac-


14

Figure 3. Thermal flux density in head phantom (Fairchild RG, Bond VP: Int J Radiat Oncol Biol Phys 11: 831–840, 1985).

tors produce neutrons of greater and lesser energies, as well as contaminating energetic photons. The latter contribute to the dose to normal tissue and must be minimized by the process of beam optimization using moderator/filter assemblies. Their function is to shift the energies of the neutrons from the fast or high energy range to the epithermal (1eV–10keV) range and to reduce the contribution of the low LET gamma rays from the reactor core. These assemblies are beginning to meet the objective of maximizing the high LET radiation generated within the tumor while ensuring that normal tissue tolerance for both high and low LET radiation is not exceeded. Thus, the twin limitations that adversely affected the earlier clinical trials in the United States, namely inadequate boron compounds and neutron beams that lacked sufficient penetrability, are now being addressed. With respect to compound development, it is clear that better agents are needed that will show higher tumor/brain and tumor/blood ratios, achieve sufficient intracellular concentrations, ideally, become bound or incorporated into tumor DNA, persist with longer retention times in the tumor, and demonstrate lower concentrations in normal dose limiting cells (i.e., vascular endothelium) in the path of the neutron beam. Furthermore, it is essential

that such compounds be able to cross the normal BBB and target those neoplastic cells that may be protected by this barrier. The key questions are how can this objective be attained? What types of compounds will show such properties? What should be the route of administration, and/or how can the BBB be manipulated? In effect, what compounds should be designed, synthesized, and evaluated which may possess the requisite properties for achieving z 109 boron atoms per tumor cell? Compounds can be divided into two broad categories: (1) low molecular weight agents, and (2) high molecular weight species. One approach with low molecular weight compounds is to synthesize boron analogues of what may be termed cellular building blocks. The rationale for synthesizing such compounds is that brain tumor cells are either metabolically more active or have higher mitotic indices compared to normal brain cells, and therefore may require such precursors, provided the analogues simulate the natural compound. Included among these are boronated phospholipid ethers that may selectively accumulate in tumor plasma membranes [23], boron-containing amino acids that may be incorporated into tumor proteins [24], and boroncontaining nucleosides that can be converted to nucleotides and subsequently incorporated into DNA and RNA [25]. Other approaches have involved the development of porphyrins [26], DNA intercalators [27], radiation sensitizers [28], and polyamines [29]. With respect to macromolecular species, work has progressed with the synthesis of boronated liposomes [30], low-density lipoproteins [31], antisense oligonucleotides [32], monoclonal antibodies and their fragments, bispecific antibodies [33], and tumor receptor binders such as epidermal growth factor (EGF) [34]. In all cases, as previously stated, it is essential that the agents be able to cross the BBB and target the malignant cells, whether or not the barrier is impaired. This requirement applies to both low and high molecular weight delivery agents. High molecular weight species, due to their size, may lack the ability to cross this barrier; and, for this reason, BBB disruption has been proposed as a means for achieving this objective [35]. With respect to neutron beams and the radiation therapy procedure, significant progress has been


15 made. Because the patient must be treated in a reasonable length of time, the designers of the beams are forced to make compromises in the process of beam optimization. Since the neutron fluence is the product of the neutron flux and the treatment time, modification of the beam’s parameters to optimize beam quality at the expense of a reduced neutron flux may be desirable, but only if radiation treatment times are not excessive. However, optimization of beam quality is hampered by our limited knowledge of the radiobiological effects of BNCT. Furthermore, such optimization is complicated by the impact of the subcellular localization of the various boron compounds and our lack of information regarding the boron microdistribution in different GBM cells. Epithermal rather than thermal neutron beams are the beams of choice. Whereas the energy for thermal neutrons is 0.025 eV, epithermal neutrons have an incident energy range between 1eV and 10keV. Each beam emanating from an individual reactor is unique and is composed not only of those neutrons with the desired spectral characteristics, but is contaminated by those with higher and lower energies and by gamma rays. The energies of the neutrons, their percentage composition, and the gamma ray component arise from the material composition of the reactor and the various filters and moderators placed in the path of the incident beam and are affected by the reactor geometry. Nuclear reactors currently are the only source of neutrons for BNCT. The limited number of nuclear reactors possessing adequate fluxes has led to a consideration of the use of fission plate technology that could be applied to reactors that otherwise would not generate a sufficient epithermal flux [36, 37]. The use of fission plates increases the neutron flux and thereby would expand the number of existing reactors that could be adapted for BNCT. Isotopic sources, such as 252Cf [38], also have been proposed as a potential source of neutrons. A limitation is the actual size of the source required to produce the needed neutron flux. Another possible source of neutrons is accelerators [39, 40]. Their development is predicated on the unequivocal demonstrations that BNCT will become a useful treatment modality. Since it is highly unlikely that new nuclear

reactors will be located near major clinical facilities, the development of compact accelerators that could be housed in radio-oncology centers is being actively considered. One possible source of such neutrons is the use of 2.5MeV protons in the 7Li (p,n)7Be reaction. To obtain neutron beams of suitable intensities, proton beam currents in the range of 10–30ma may be required. The magnitude of these currents necessitates the development of an appropriate cooling system capable of dissipating the heat produced by the bombardment of the lithium target. Furthermore, the target must remain intact under these conditions, and adequate shielding must be provided to ensure personnel safety. These issues are currently being addressed. In the treatment of tumors at the midline of brain, 5–8cm deep, epithermal beams with increased energy may be required. Our knowledge of the normal tissue tolerance to these beams is evolving [41, 42]. Yet it is complicated by the fact that any new beam/drug combination may have different effective dose distributions or may produce damage in different normal tissue compartments. Presently, physical doses are calculated using well-documented and verified radiation transport codes. However, the lack of knowledge of the radiobiological effectiveness (RBE) of BNCT in different tissues with varying physical doses and dose rate makes a precise determination of the effective (or RBE) radiation dose a complex process. Adding to this complexity is the so-called ‘compound factor’ [43]. This factor relates the impact of the cellular and subcellular localization of different boron compounds and their metabolites on the radiobiological effects of the high LET boron capture dose. In conventional radiation therapy, dose escalation is used to attain an optimal balance of tumor control versus potential damage to normal tissue. In BNCT, this balance is in large part due to sufficient uptake of boron-10 in tumor and lack of uptake in normal tissue. Escalation of radiation is ineffective in cells without boron. The clinical use of BNCT is at such a preliminary stage of development that it is necessary first to define the safe level of exposure of normal brain to the mixed radiation field and the high LET particles generated with the particular boron compounds involved. At the same time, what


16 is the effect on tumor? Since therapeutic success may require that a very significant percentage, if not all subpopulations, of tumor cells have adequate concentrations of a boron compound, it seems highly unlikely that a single administration of a particular agent will achieve that objective. This may be especially the case for a heterogenous population of tumor cells at various stages in the cell cycle. A case therefore can be made for multiple administrations not only of a single drug, but ultimately of a combination of various agents possessing differing mechanisms for achieving the targeting of tumor cells. Just as cancer chemotherapy requires multiple drugs with varying time patterns for dosing, so too BNCT may ultimately require a similar method for ensuring adequate tumor cellular uptake of boron compounds. One advantage of multiple dosing is the opportunity that it affords for fractionation in BNCT. This can provide an additional and important margin of safety to normal brain, which would be most sensitive to large radiation doses per fraction. Fractionation will permit repair of damage from low LET radiation, arising from both the in situ hydrogen capture reaction and the gamma radiation from the reactor core without compromising the tumor effect. The effect on the tumor must largely arise from the high LET particles generated in the boron-10 capture reaction, and the damage that it produces is neither DNA reparable nor fractionation dependent. Although current clinical studies are attempting to determine the effectiveness of BNCT in tumor control using a single dose regimen, it must be borne in mind that this may not be the optimal treatment schedule.

Conclusions From the preceding discussion, it should be apparent why BNCT is such a highly complex treatment modality. In view of the current dismal results obtained in the treatment of GBM and metastatic brain tumors, the focus of BNCT has been largely designed to treat CNS malignancies. The first objective is to determine whether BNCT has clinical efficacy with these therapeutically refractory tu-

mors and only then can treatment of other solid tumors for which existing therapies are ineffective be considered. The potential utility of BNCT can be determined only by carefully controlled clinical trials and objective comparison with existing treatment modalities that currently are in use. BNCT has been used clinically in Japan since 1968, and in the United States since 1995 and may be initiated in Europe within the next year. When these studies have been completed, it finally should be possible to conclude whether or not BNCT has a place in treating presently incurable tumors of the CNS.

Acknowledgements The authors wish to thank David Carpenter, Joan Dandrea and Brain Rugg for their assistance in the preparation of this manuscript. We also want to acknowledge support for our research by the U.S. Public Health Service Grants (R01 CA-53896 and R01 CA-71033) and the U.S. Department of Energy (DE-FG02-90ER60972 and DE-AC0276CH00016).

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