Neutron Radiotherapy

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Chapter 20 Neutron Radiotherapy

The neutron was discovered by Sir James Chadwick in 1932 during an analysis of certain nuclear reactions. Shortly thereafter, investigators proposed using it to treat various human malignant diseases. There have been two main areas of clinical investigation: fast neutron radiotherapy and boron neutron capture therapy (BNCT). We briefly describe the underlying physics of each type of therapy, summarize the historical development, and discuss current clinical usage. Space permits only a brief discussion of neutron brachytherapy using californium-252 (²⁵²Cf) sources, which is in limited clinical use today.

Fast Neutron Radiotherapy

Overview

Fast neutron radiotherapy uses neutrons having typical energies of several tens of megaelectron volts (MeV) that are generated by accelerating either protons or deuterons with cyclotrons or particle accelerators and then delivering them to an appropriate target, most generally beryllium. The resulting distribution of neutrons is approximately spherically symmetric, and the beams used in therapy are collimated out in much the same manner as the photon therapy beams generated by electron linear accelerators. Fission neutrons from nuclear reactors that have energies in the range of 1 to 2 MeV can also be used to treat patients. Neutrons are neutral particles and interact directly with the atomic nuclei in tissue, producing recoil protons and nuclear fragments, which in turn create a dense chain of ionization events. For neutrons of energies used in radiotherapy, about 85% of the deposited energy is via a “knock-on” reaction (“billard-ball” type of collision) involving the hydrogen-1 (¹H) nucleus, meaning that the KERMA (kinetic energy release in matter) is larger in high-hydrogen-content tissue such as fat or myelin.

The resulting energy transfer is in the range of 20 to 100 keV/µm compared with 0.2 to 2 keV/µm for the megavoltage photons and electrons used in conventional radiotherapy. It is this higher energy transfer that gives rise to the different radiobiologic properties of fast neutrons, which are advantageous in certain clinical situations. The higher relative biologic effectiveness (RBE) accounts for the different clinical response observed with neutrons as opposed to conventional photon irradiation. Fast neutrons have RBEs in the range of 3 to 3.5 in terms of most normal tissue late effects, RBEs in the range of 4 to 4.5 in terms of damage to the central nervous system, and RBEs in the range of 8 for salivary gland malignant tumors.¹^–³ High–linear energy transfer (LET) radiation causes a dense chain of ionizing events to both strands of the DNA and therefore makes DNA repair more difficult. Furthermore, high-LET radiation from fast neutrons is less sensitive to the reduced cell killing effects of hypoxia, with there being approximately equal cell killing under normoxic and hypoxic conditions.

Patients were first treated with fast neutron radiotherapy in 1938 by Robert Stone and co-workers ⁴ at the Crocker Radiation Laboratory (later to become Lawrence Berkeley Laboratories). Two hundred forty patients were treated between 1938 and 1942. Many of these patients had received prior photon irradiation. There were significant radiation sequelae in the few long-term survivors such that clinical interest in fast neutron radiotherapy dropped off significantly for the next 20 years. Brennan and Phillips⁵ subsequently reviewed the initial work by Stone and colleagues and showed that an inappropriate value for the neutron RBE had been used in the dose calculations. Hence, many of those initial patients had been inadvertently overdosed. With a better understanding of the RBE of fast neutron radiotherapy in different tissue types, in the 1970s Catterall and coworkers^6,^7,⁸ resumed neutron clinical trials at Hammersmith Hospital in London, England. Their results indicated that many advanced head and neck cancers exhibited a good response with acceptable side effects. The interest in fast neutron radiotherapy grew so that at one point there were 39 different centers in North America, Europe, Asia, and Africa treating patients with fast neutrons. Clinical utility has been further elucidated through clinical trials and single-institution experience, and neutron radiotherapy now has fairly well defined and limited indications. There are currently only seven operating fast neutron radiotherapy centers throughout the world. These are listed in Table 20-1, along with some of their more important characteristics.

TABLE 20-1 Location of Operating Fast Neutron Radiotherapy Centers, 2009

Location	Beam Reaction	Comments
United States
University of Washington Medical Center, Seattle, Washington	50 MeV p→Be	Isocentric gantry and multileaf collimator
Fermi Laboratories, Batavia, Illinois	66 MeV p→Be	Horizontal beam, fixed collimators with blocking inserts
Europe
Tomsk Polytechnical University, Tomsk, Russia	Cyclotron	Mean neutron energy 6.3 MeV
Technisch Universtät Munich, Munich, Germany	Fission neutrons	FRMII reactor, horizontal beam with multileaf collimator, mean neutron energy 1.9 MeV
Institute of Physics and Power Engineering, Obninsk, Russia	Fission neutrons	Horizontal beam
Asia
National Institute of Radiological Sciences, Chiba, Japan	30 MeV d→Be	Vertical beam, multileaf collimator
Africa
National Accelerator Centre, Faure, South Africa	66 MeV p→Be	Isocentric gantry and jaw collimator

Be, beryllium, d, deuteron, FRMII, Forschungs-Nuetronenquelle Heinz Maier-Leibnitz; MeV, million electron volt; p, proton.

Below is a summary of clinical situations and tumor histologic types for which neutrons have been shown to be advantageous compared with standard photon irradiation.

Salivary Gland Tumors

The therapeutic advantage of fast neutron radiotherapy over conventional radiotherapy is best established in salivary gland tumors. The RBE for salivary gland tumors is approximately 8, whereas for surrounding normal tissues, the RBE is 3 to 3.5.¹ A typical neutron dose for a salivary gland cancer is approximately 18 to 20 nGy (neutron Gray). The approximate equivalent photon dose is 60 to 70 Gy equivalents (GyE) as far as normal tissues are concerned but it is in the range of 150 to 160 GyE as far as the tumor is concerned. The therapeutic gain factor for salivary gland tumors is therefore in the range of 2.3 to 2.6.

Early single-institution studies showed neutrons to be beneficial in the treatment of salivary gland tumors. These results led to a prospective randomized trial sponsored by the Radiation Therapy Oncology Group (RTOG) and the Medical Research Council (MRC) of Great Britain.⁹ Local control at 10 years was improved in the neutron arm (56% vs. 17%; p = .009). The final report showed a trend toward increased median survival of about 8 months in the neutron arm, but this was not statistically significant. However, the cause of death differed between the two subgroups. Metastatic disease was the main cause of death for the neutron patients, whereas local/regional tumor failure was the main cause of death for the photon patients. Of note, the study was stopped early for ethical reasons when 2-year survival data showed a strong trend in favor of the neutron patients. Local tumor control curves for this study are shown in Figure 20-1.

Figure 20-1 Actuarial locoregional control curves for patients with unresectable salivary gland tumors from the Radiation Therapy Oncology Group/Medical Research Council (RTOG/MRC) randomized study (80-01). The difference between the neutron curve (red dashed line) and the photon curve (blue solid line) is statistically significant at the p = .009 level.

Adapted from Laramore GE, Krall JM, Griffin TW, et al: Neutron versus photon irradiation for unresectable salivary gland tumors. Final report of an RTOG-MRC randomized clinical trial, Int J Radiat Oncol Biol Phys 27:235, 1993.

The University of Washington experience was reviewed by Douglas and colleagues.^10,¹¹ Two hundred seventy-nine patients treated with curative intent were included in the analysis. A majority (263 patients) had evidence of gross disease, with 141 having major salivary gland neoplasms and 138 having minor salivary gland neoplasms. The 6-year actuarial cause-specific survival rate was 67%. On multivariate analysis, stage I/II disease, minor salivary gland primary tumors, lack of base-of-skull involvement, and primary (rather than recurrent) disease were associated with improved survival rates. Improved locoregional control was associated with tumors having the following characteristics: greatest diameter less than 4 cm, no base-of-skull invasion, prior surgical resection, and/or no previous radiation therapy. The 6-year actuarial rate for freedom from the development of metastases was 64% for patients without lymph node involvement or base-of-skull involvement. There was a 6-year actuarial rate of 10% for developing RTOG grade 3 or 4 toxicity. Cause-specific survival curves for the major salivary gland patients as a function of tumor size are shown in Figure 20-2.

Figure 20-2 Actuarial cause-specific survival curves as a function of tumor size for patients with major salivary gland tumors treated with curative intent at the University of Washington neutron treatment facility. The blue solid curve depicts the results for patients with tumors smaller than 4 cm in the greatest diameter, and the dashed red curve depicts the results for patients with tumors larger than 4 cm in the greatest diameter. The difference between the two curves is statistically significant at the p <.0001 level.

Adapted from Douglas JG, Lee S, Laramore GE, et al: Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors, Head Neck 21:255, 1999.

The poorer outcome of salivary tumors with base-of-skull involvement appears to be the result of the need to reduce the dose to portions of tumors that are adjacent to critical central nervous system structures (recall that the RBE for fast neutrons for central nervous system tissue is 4 to 4.5). With a standard 20-nGy dose to the involved site, the dose to the temporal tips could be approximately 80 photon GyE. Reducing the temporal lobe dose to a safe level sometimes necessitated blocking portions of tumor. In an attempt to compensate for the reduced neutron dose, a stereotactic radiosurgical boost with photon radiation has been instituted at the University of Washington. At 40 months there was improved local control compared with historically treated patients with skull base invasion who did not receive a stereotactic radiosurgical boost (82% vs. 39%; p = .04).¹² Complications appear to be acceptable.

The use of both neutrons and photons in a composite “mixed beam” treatment has been explored by Huber and associates ¹³ in a series of patients with advanced adenoid cystic carcinomas treated at the Heidelberg neutron facility. They found a 5-year local control rate of 75% for patients treated with neutrons alone compared with 32% for patients treated with “mixed beam” irradiation or with photons alone. It appears that patients who have a greater portion of their treatment with neutrons fare better. Distant metastatic disease once again prevented improved local control from translating into an increase in overall survival rates.

The neutron facility in Orleans has reported similar results for 59 patients treated with fast neutron radiotherapy.¹⁴ The 5-year local control rate was 69.5%, with a crude 5-year survival rate of 66% and a 5-year tumor-free survival rate of 64.5%.

Prostate Cancer

Prostate cancer is another tumor for which there has been significant clinical work using fast neutron radiotherapy. The National Cancer Institute (through RTOG 77-04) conducted a randomized trial for patients with T3, N0/N1 disease.¹⁵ One arm received a mixed beam (neutron/photon) dose to 70 GyE versus a second arm that received standard photons to 70 Gy. At the 10-year endpoint, survival rates (46% vs. 29%, p = .04) were improved in the mixed beam arm. There was also improved locoregional control (70% vs. 58%, p = .03) for the mixed beam subgroup. There was no difference in the rate of significant complications between the two arms. Survival curves for the patients in this study are shown in Figure 20-3.

Figure 20-3 Actuarial survival curves for patients with locally advanced prostate cancer treated on Radiation Therapy Oncology Group (RTOG) protocol 77-04. The mixed (neutron and photon) beam group is shown by the dashed red curve, and the photon control arm is shown as the solid blue curve. The difference between the curves is statistically significant at the p = .04 level.

Adapted from Laramore GE, Krall JM, Griffin TW, et al: Fast neutron radiotherapy for locally advanced prostate cancer, Am J Clin Oncol 16:164, 1993.

A follow-up randomized trial was conducted that compared 70-Gy standard photon irradiation with 20.4-nGy fast neutron therapy. This was carried out by the National Cancer Institute (NCI)–sponsored Neutron Therapy Collaborative Working Group (NTCWG) and included patients with high-grade T2 tumors or T3 to T4, N0 to N1, M0 tumors of any grade.¹⁶ With a median follow-up of 68 months, the 5-year actuarial locoregional failure rate was 11% for neutrons versus 32% for photons (p <.01). Actuarial overall survival and cause-specific survival rates were statistically equivalent. The incidence of severe complications was higher in the neutron group than in the photon group (11% vs. 3%). Complications were less severe and fewer in the centers that had more sophisticated beam-shaping abilities. Local failure curves for the patients in this study are shown in Figure 20-4.

Figure 20-4 Actuarial percent local failure curves for patients with locally advanced prostate cancer treated on Neutron Therapy Collaborative Working Group (NTCWG) protocol 85-23. The group treated with neutrons is shown as the dotted green curve, and the group treated with photons is shown as the dashed blue curve. The difference between these two curves is statistically significant at the p <.01 level. A local control curve (solid red line) for photon-treated patients from another Radiation Therapy Oncology Group study (RTOG 75-06) is shown for comparison. There is no statistical difference between the latter curve and the photon control arm of the neutron study.

Adapted from Russell KJ, Caplan RJ, Laramore GE, et al: Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer. Results of a randomized prospective trial, Int J Radiat Oncol Biol Phys 28:47, 1993.

Following the randomized trials, additional studies were conducted at several centers in the United States,^17,^18,^19,^20,²¹ Europe,^22,²³ and Asia.^24,²⁵ These single-institution results showed good local and regional control and appeared to corroborate the results of the randomized trials described earlier.

Sarcomas

Sarcomas are generally considered to be among the more “radioresistant” histologic types of tumors and so would fall into the category of tumors thought to be more responsive to high-LET radiation.¹ A retrospective review by Schwarz and colleagues²⁶ reports on 1171 soft tissue sarcoma patients from 11 European centers treated with fast neutron radiotherapy. In those patients with either inoperable tumors or gross disease after surgery, the local control rate was approximately 50%. Toxicity was higher than what was generally seen with photon irradiation. The local control rates were thought by the authors to be better than what would have been expected with standard radiotherapy. This conclusion is supported by other single-institution studies.²⁷

Other Tumor Types

Fast neutron radiation has been tested on a variety of other tumor types. Generally, the rationale for the use of fast neutrons came from trying to overcome a perceived limitation of standard photon irradiation. A good example of this is malignant glioma of the brain. Dose-escalation studies with photons have failed to increase overall survival rates.²⁸ By definition, glioblastoma multiforme tumors have associated areas of necrosis that are often surrounded by regions of hypoxia, which might make the tumors more radioresistant. Studies of malignant gliomas in the 1970s and 1980s used neutrons either alone or in combination with photons.²⁹ None of these initial trials showed an improvement in overall survival rates with the addition of neutrons. However, with relatively high doses of fast neutrons alone, autopsy and second-look surgical data indicated that tumor cells were sterilized in the treated region.³⁰ Unfortunately, there was also significant coagulative necrosis caused by the neutron irradiation, which indicated too much damage to normal brain tissue. A more recent study used fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning to determine the final boost volume that received 18 nGy.³¹ Only 10 patients were treated and all exhibited tumor progression by 39 weeks, perhaps because of the restricted fields that were employed. Gliosis and microvascular sclerosis consistent with radiation injury were noted in regions of the contralateral brain receiving 6 to 10 nGy. Much of the current interest in neutron radiotherapy for malignant gliomas is focused on BNCT, which is discussed later in this chapter.

Squamous cell carcinoma of the head and neck region is another tumor for which neutrons have been used to try to overcome the relative radiation resistance of hypoxic cells. However, randomized studies and several single-institutional trials in Europe and the United States failed to show a significant improvement in locoregional control with the use of neutrons compared with standard photons. Furthermore, the side effects were generally more severe.

Summary

Neutron radiotherapy is best used in the treatment of certain tumors that exhibit a “resistance” to standard low-LET radiotherapy. The niche that it occupies is small, but it remains a highly important treatment option for small numbers of patients for whom it appears to be better than more traditional forms of treatment. Examples are patients with inoperable or recurrent salivary gland malignant tumors or in high-risk situations where there has been an incomplete surgical extirpation or where inoperable or incompletely resected sarcomas of bone, cartilage, and soft tissue or locally advanced prostate cancers—particularly those that are not hormonally responsive—have been found. In highly selected circumstances, it may also be beneficial in the treatment of metastases from melanoma and renal cell cancer. Future research may extend these indications.

Boron Neutron Capture Therapy

Overview

Conceptually, boron neutron capture therapy (BNCT) is a “magic bullet” approach to treating tumors. Pure beams of very low energy neutrons do not directly deposit much energy in tissue via collisions but rather interact via nuclear transmutation reactions. The basic idea is to selectively attach to the cancer cells a nuclide having a large cross section for capturing a thermal neutron. The nuclide then undergoes a nuclear reaction with the localized release of a substantial amount of energy. In principle, this kills the “tagged” cell but does not damage the surrounding “untagged” normal cells. Although there is ongoing work in developing high-current particle accelerators to produce low-energy thermal or epithermal beams for BNCT, at the present time, all clinical work is being done using moderated neutron beams from nuclear reactors. There are other nuclides besides boron-10 (¹⁰B) that have a high neutron capture therapy cross section, and some of these (e.g., gadolinium-157 [¹⁵⁷Gd]) are of interest in neutron capture therapy for cancer. However, we will confine our discussion to BNCT. We also confine ourselves to the clinical perspective and do not attempt to describe the ongoing research in radiobiology or compound development or the physics research into nonreactor sources of appropriate beams.

Historical Perspective

The basic idea for BNCT dates to 1936, when Locher ³² proposed treating malignant tumors with low-energy thermal neutrons via a capture process with ¹⁰B. A few years later, Kruger³³ and Zahl and colleagues³⁴ experimentally verified some of the basic tenets of this concept and demonstrated the high RBE of the resulting helium-4 (⁴He) and lithium-7 (⁷Li) fission fragments. The theoretical advantage of “tagging” the tumor-specific carrier with an innocuous substance such as ¹⁰B and then activating it, rather than “tagging” it with a toxic compound such as ricin, is that the “binary approach” is more forgiving of other body tissues that might also display some avidity for the carrier agent. In the real world, the thermal and epithermal beams produced by nuclear reactors are contaminated with gamma rays and fast neutrons, which can cause considerable normal tissue damage even in the absence of a high ¹⁰B concentration.³⁵ Moreover, even in the absence of such beam contaminants, nuclear species such as ¹H, nitrogen-14 (¹⁴N), and chlorine-35 (³⁵Cl), which are commonly found in tissue, interact with thermal neutrons via capture events of their own, and their reaction products cause biologic damage to non–¹⁰B-containing normal tissues. Although the respective capture cross sections for these commonly found nuclei are much lower than for ¹⁰B and other nuclear species of interest for neutron capture therapy, the concentrations of these commonly found nuclei are many orders of magnitude greater than the concentrations of ¹⁰B. Hence, reactions involving these nuclides can result in an appreciable tissue dose, even in the absence of ¹⁰B. The key to BNCT as a practical therapy is the development of compounds that localize specifically in tumors and deliver sufficient ¹⁰B concentrations to yield a significant therapeutic advantage compared with the radiation doses delivered to normal tissues.

Early Clinical Studies

The first set of human clinical trials was carried out in the 1950s at Brookhaven National Laboratory using ¹⁰B-enriched, boric acid derivatives.^36,³⁷ These compounds yielded high concentrations of ¹⁰B in the blood at the time of irradiation and unfortunately produced relatively low ¹⁰B levels in the tumors. This resulted in considerable blood vessel endothelial damage and no therapeutic benefit from treatment either in these trials or in subsequent trials that were carried out in the 1960s.^38,^39,⁴⁰ Interest in the technique waned until Hatanaka and others in Japan⁴¹ reinstituted BNCT for malignant gliomas using a different ¹⁰B-carrier, ¹⁰B-sodium-mercaptoundecahydrododecaborate (BSH). This compound produced better tumor-to-blood boron ratios than the compounds used in the prior Brookhaven National Laboratory studies and the treatments caused less damage to normal brain tissue. Favorable reports regarding the efficacy of BSH^41,^42,⁴³ led to renewed worldwide interest in the technique. Many patients have received BNCT treatments using thermal neutron beams from various reactors in Japan, but to date, no randomized clinical trials have been carried out. An analysis of the RTOG database by Curran and colleagues⁴⁴ has demonstrated that there are some subsets of patients with high-grade gliomas who will do well with conventional photon irradiation. A few years ago, an analysis of a subset of patients from the United States who were treated with BNCT in Japan showed no improvement over that which would have been expected with conventional therapy after correcting for the appropriate prognostic factors.⁴⁵ A comparison of the survival rates of these patients with a pseudo-matched group from the RTOG data base is shown in Figure 20-5. The prognostic factors identified by Curran and colleagues⁴⁴ were used to generate these curves. There is no statistical difference between the two curves. Moreover, review of the data for the entire group of evaluable patients showed that in all except one patient there was a documented tumor recurrence within the primary radiation field.⁴⁵ The only long-term survivor in this group of American patients had an anaplastic astrocytoma and fell into the most favorable category I of Curran and coworkers.⁴⁴

Figure 20-5 Actuarial survival curves for a group of 10 patients from the United States with glioblastoma multiforme (GBM) histology who were treated with boron neutron capture therapy (BNCT) (solid blue curve) and the expected survival curve for a matched cohort who received conventional treatment according to various Radiation Therapy Oncology Group study (RTOG) protocols (dashed red curve). There is no statistically significant difference between the two curves.

Adapted from Laramore GE, Spence AM: Boron neutron capture therapy [BNCT] for high grade gliomas of the brain. A cautionary note, Int J Radiat Oncol Biol Phys 36:241, 1996.

There is no doubt that many aspects of the early Japanese BNCT clinical research program were suboptimal. The use of a poorly penetrating beam of thermal neutrons meant that an open craniotomy was required to expose the tumor bed. Due to the low neutron fluxes, treatment times of 4 to 8 hours were required to deliver a surface fluence of approximately 10¹³ neutrons/cm², and during treatment the patient had to be under general anesthesia with the brain exposed in a converted operating room adjacent to the nuclear reactor. Although BSH is conceptually attractive as a ¹⁰B-carrier agent in that it is excluded from normal brain tissue by the blood-brain barrier, typical tumor boron concentrations for glioblastoma multiforme were in the range of only 15 to 25 µg/g. It is now possible to improve on many of these shortcomings.

Modern Clinical Trials

In the modern era, clinical trials have been conducted in Japan, Europe, Argentina, and the United States. Most of this work has dealt with the treatment of malignant brain tumors and metastatic melanomas.

In Japan, there were three reactor facilities involved in patient treatments: (1) KUR in Osaka, (2) MITR in Musashi, and (3) JRR-4 at the Japan Atomic Energy Research Institute in Ikargi.⁴⁶ Although most patients have been treated using thermal neutron beams, the KUR facility has been modified to produce a higher-energy epithermal beam allowing treatment through the intact skull. The majority of the patients have been treated for various types of brain tumors using BSH as the ¹⁰B-carrier agent and with a single fraction of neutron radiation. A report by Nakagawa and colleagues⁴⁷ shows that in the subset of glioblastoma multiforme patients, 12% of treated patients lived longer than 2 years. Depending on other prognostic factors, this may or may not be better than expected with more conventional forms of treatment. Currently only the KUR and JRR-4 reactors are treating patients.

There were several reactor facilities in Europe with BNCT clinical programs for malignant brain tumors, all using epithermal neutron beams. The program that treated the most patients was based at the HFR reactor in Petten (the Netherlands) and was directed by the European Collaboration on Boron Neutron Capture Therapy. BSH at 100 mg/kg was used as the ¹⁰B-carrier. Researchers conducted a phase I dose-searching study restricted to the subsets of glioblastoma multiforme patients whose expected median survival time with conventional radiotherapy would be less than 10 months. Unlike the other ongoing treatment regimens, which employed a single BNCT treatment, the Petten program used four fractions requiring multiple administrations of the boron-carrier compound. BNCT dose reporting is complex, and the Petten group has chosen to specify each component of the radiation field separately rather than state a Gray-equivalent dose.⁴⁸ The starting dose from the ¹⁰B component was set at 80% of the dose that produced neurologic changes in a dog brain study, D_B = 8.6 Gy. The other components of the radiation dose were limited to D_n < 0.9 Gy, D_N < 1.1 Gy, and D_g < 5.8 Gy, where D_n is the neutron-absorbed dose delivered by the thermal, epithermal, and fast neutrons and the charged particles produced by their reactions, D_g is the gamma ray absorbed dose, and D_N is the absorbed dose from the protons produced by the ¹⁴N capture reaction. Twenty-five patients were entered into the initial dose arm of the study, with 21 actually receiving BNCT treatment.⁴⁹ The median survival time of the BNCT-treated patients was 31 weeks, with 6 patients alive at the time of a preliminary report. All 21 patients exhibited tumor recurrence. A second BNCT program is based at the FiR No. 1 reactor in Helsinki, Finland. The initial protocol was a phase I dose-searching study that used L–para-boronophenylalanine (BPA) in a fructose solution at 290 mg BPA/kg as the B-carrier. Only a single treatment was given using two radiation fields. Thus far, 10 patients have been treated with tumor doses between 35.1 and 66.7 GyE. This effective dose has been determined using weighting factors for each of the radiation components (see Kankaanranta and colleagues⁵⁰ for specific details). With a median follow-up of 9 months, 7 of 10 patients had recurrent or persistent tumor, with the median time to tumor progression being 8 months.⁵⁰ The toxicity in both of the European trials was thought to be acceptable, making future escalation of the radiation dose possible. Small numbers of patients were also treated at Studsvik Medical AB in Uppsala University⁵¹ and at the Nuclear Research Institute in the Czech Republic.⁵² Currently, only the FiR No. 1 reactor is treating patients.

After approximately a 30-year hiatus, the first “modern era” BNCT clinical program in the United States was begun at the Massachusetts Institute of Technology (MIT) research reactor in collaboration with Tufts Medical Center. The first patient was treated in September 1994. This project was under the clinical direction of the New England Deaconess Hospital. Treatments were delivered using an epithermal beam with BPA as the ¹⁰B-carrier agent. Between 1996 and 1999, a total of 22 patients with intracranial lesions, either glioblastoma multiforme or metastatic melanoma, were treated.⁵³ The initial clinical trial was a dose-searching toxicity study with the target dose ranging between 8.8 and 14.2 GyE. At the higher radiation doses, the time required to deliver the dose ranged up to 3 hours. At the higher dose levels, significant skin and mucosal reactions were observed. No adverse effects were noted due to the BPA administration, and no long-term complications relating to the BNCT treatment were noted. Some tumor responses were noted in the patients with metastatic melanoma, but there was no obvious prolongation of survival rates in either group of treated patients. This facility is no longer treating patients.

A second clinical BNCT program focusing on high-grade gliomas of the brain was initiated at Brookhaven National Laboratory. This program differed from the Japanese glioma program in two main respects: (1) a higher-energy epithermal neutron beam was used rather than a thermal neutron beam, and (2) a different ¹⁰B-carrier agent (BPA) was used rather than BSH. The epithermal beam meant that patients could be treated without recourse to a craniotomy and intraoperative irradiation and that more deeply located tumors could be given adequate doses. It was expected that BPA would produce higher tumor ¹⁰B concentrations than could be achieved with BSH. Based on ¹⁰B blood levels, it appeared that tumor ¹⁰B concentrations of approximately 35 to 50 µg/g were achieved. However, unlike BSH, BPA is not excluded from the normal brain by the blood-brain barrier, and tumor enrichment depends on other mechanisms of selective uptake (perhaps relating to an enhanced amino acid transport system). A dose-escalation approach was used. Prior to June 1996, all patients were treated using a simple appositional field with a single treatment fraction being given. A critique of this early Brookhaven National Laboratory treatment technique indicated significant deficiencies in the basic approach relating to the inability to achieve a tumor dose adequate to sterilize glioblastoma multiforme tumors using a single appositional field.⁵⁴

Between September 1994 and May 1999, 53 patients with primary glioblastoma multiforme received BPA-fructose–mediated BNCT at Brookhaven National Laboratory using one, two, or three irradiation fields on a sequential, dose-searching protocol. The median age for the subjects treated with one field was 56.5 years, with a median tumor volume of 20.5 cm³ (2 to 70 cm³) and a median Karnofsky Performance Status (KPS) of 80. The volume-weighted average radiation dose to normal brain (ABD) varied from 1.9 to 4.1 GyE for one field, from 4.1 to 6.6 GyE for two fields, and from 6.7 to 9.5 GyE for the three-field group.

Fifty of the 53 subjects have exhibited tumor persistence/recurrence within the treatment volume.⁵⁵ The median time to progression was independent of dose. In fact, there was a significant trend toward worse local control in subjects treated using three fields. Survival as an endpoint was found to be more dependent on the aggressiveness of the postrecurrence treatment than the BNCT dose given and, as such, was not a useful indicator of treatment-dependent tumor control. The functional brain tolerance was reached in the three-field group. All except one patient treated with three fields exhibited significant acute or subacute functional neurologic toxicity at average brain doses as low as 6.7 GyE. This may indicate a “volume effect” in that multiple fields generally treat a larger volume of normal brain to a lower dose compared with when a single field is used. The early stopping criterion of a more than 20% incidence of grade 3 or 4 toxicity (RTOG and European Organization for Research and Treatment of Cancer [EORTC] criteria) was reached during this study. However, no significant tumor response was observed in the patients treated to minimum tumor doses above those predicted by Laramore and coworkers^54,55 to be therapeutic. We also note that preclinical studies using a 9L rat gliosarcoma model showed significant tumor response of the tumor to BPA-fructose–mediated BNCT at comparable doses.⁵⁶ Hence, neither the preclinical radiobiologic studies nor the mathematical modeling based on fast neutron data provided an accurate guide to the necessary therapeutic dose. The Brookhaven National Laboratory clinical program is no longer in operation.

In parallel with the BNCT program for malignant gliomas, a second area of major interest is the treatment of malignant melanoma metastatic to the brain. This work was instigated by Mishima and associates ^57,⁵⁸ in Japan. They used BPA as the ¹⁰B-carrier agent with a single fraction of thermal neutrons. BPA acts as a dopamine analog in the melanin synthetic pathway and concentrates well in pigmented tumors. Initial reports describe good clinical results with this treatment,^59,⁶⁰ but no randomized trials have been performed. Reports from the MIT/Massachusetts General Hospital program indicate that responses are better in this setting than in the treatment of glioblastoma multiforme, which is consistent with BPA being better suited to the treatment of pigmented tumors. Under the auspices of the Atomic Energy Commission of Argentina, a program for the treatment of metastatic melanoma has been instituted at the RA-6 research reactor in San Carlos de Bariloche, and this program is still clinically active.⁶¹

A very interesting approach to the treatment of liver metastases was begun at the University of Pavia in Italy. The patient is infused with BPA, and the diseased liver is extirpated and irradiated in the reactor and then reimplanted into the patient. Two patients have been treated in this manner, with one long-term survivor at 3 years from the time of the procedure. Model calculations indicate that it may be possible to perform this treatment without first removing the liver.⁶²

Summary

To date there is no convincing evidence that BNCT offers a therapeutic advantage over conventional treatments for glioblastoma multiforme. Reactor-based treatment centers are sufficient in number to conduct well-designed clinical trials to provide a “proof of concept” but certainly will not be adequate to treat large numbers of patients in the event that a therapeutic advantage is demonstrated. In this event, accelerator-based sources must be designed and placed in hospital settings. The main hurdle at the present time is the lack of tumor-specific ¹⁰B-carrier agents. The only compounds currently approved for human trials are BSH and BPA—both of which are suboptimal in many ways. Support of research in compound development will be key to further development of the field.⁶³

Californium 252 Brachytherapy

Californium was the sixth transuranium element that was produced by a team at the Lawrence Berkeley Laboratories in 1950 by bombarding a curium target with α particles. The particular isotope used in radiotherapy, californium-252 (²⁵²Cf), is produced in high-neutron flux reactors and is made available for peaceful uses by the U.S. Department of Energy. ²⁵²Cf is a neutron-rich isotope that has a half-life of 2.647 years. It decays either by α-particle emission or by spontaneous fission with a branching ratio of 96.9% to 3.1%. It is a highly prolific neutron emitter with a spectrum of energies similar to that produced by nuclear reactors. Although its use in medicine requires significant radiation protection precautions, it is theoretically attractive for brachytherapy applications wherein high-LET radiation is advantageous from a radiobiologic aspect. It has also been proposed as a hospital-based teletherapy source for BNCT applications.

Gynecologic applications of ²⁵²Cf brachytherapy were explored by Maruyama and associates,⁶⁴ who developed appropriate dosing schedules. More recently, Tacev and colleagues⁶⁵ reported on long-term results of a randomized trial for patients with advanced cervical cancer (stages IIB and IIIB) that compared ²⁵²Cf brachytherapy with a supplementary gamma ray boost of 16 Gy with conventional brachytherapy alone with gamma ray–emitting radium-226 (²²⁶Ra) or cesium-137 (¹³⁷Cs) sources following 40-Gy external beam radiotherapy. Using an RBE of 6 for the ²⁵²Cf neutrons, point A doses of 56 GyE were given with the implants. Two hundred seventy-seven patients were entered into the study, and there was an improved 5-year survival rate in the group receiving the ²⁵²Cf implant (75.2% vs. 56.3%; p < .001).

Also of note is a pilot study using ²⁵²Cf interstitial brachytherapy in 56 patients with high-grade gliomas of the brain.⁶⁶ After surgical debulking, catheters were placed under CT guidance followed by ²⁵²Cf placement. A dose of 3 Gy was given over 4 to 6 hours to the residual tumor, and then patients received 60-Gy to 70-Gy doses of conventional external beam radiotherapy. The median survival time was only 10 months, and recurrent tumor was found in all patients who died and were autopsied. Given the dose inhomogeneties and the relatively small amount of neutron radiation given, this outcome is not surprising.