Radiologic validation of a fast neutron multileaf collimator.

Teletherapy with high linear energy transfer radiations (LET), perhaps more than with low LET types, requires careful beam collimation to limit effects to normal structures. Intensity modulated techniques may also hold promise in this regard. Accordingly, a remote computer-controlled, high-resolution multileaf collimator (MLC) is placed into service at the Gershenson Radiation Oncology Center's fast neutron therapy center of the Karmanos Cancer Institute, Detroit, Michigan. Prior to clinical application the basic radiological properties of the fast neutron MLC are studied. Complicating the evaluation is the mixed neutron and gamma radiation field environment encountered with fast neutron beams. As a reference the MLC performance is compared to an existing multirod collimator (MRC) used at the facility for more than ten years. The MLC aggregate transmission is found to be about 4%, slightly outperforming the MRC. The measured gamma component for a closed collimator is 1.5 times higher for the MLC, compared with the MRC. The different materials used for attenuation, steel and tungsten, respectively account for the difference. The geometry for the MRC is double focused whereas that for the MLC is single focused. The resulting penumbrae agree between the focused axis of the MLC and both axes of the MRC. Penumbra differences between the focused and unfocused axes were not observable at small field sizes and a maximum of about 1 cm for a 25 x 25 cm2 field at 2.5 cm depth in water. For a 10 x 10 cm2 field the focused penumbra is 9 mm, and the unfocused is 12 mm. The many benefits of the fully automatic MLC over the semimanual MRC are considered to justify this compromise.

Compact multileaf collimator for conformal and intensity modulated fast neutron therapy: electromechanical design and validation.

The electromechanical properties of a 120-leaf, high-resolution, computer-controlled, fast neutron multileaf collimator (MLC) are presented. The MLC replaces an aging, manually operated multirod collimator. The MLC leaves project 5 mm in the isocentric plane perpendicular to the beam axis. A taper is included on the leaves matching beam divergence along one axis. The 5-mm leaf projection width is chosen to give high-resolution conformality across the entire field. The maximum field size provided is 30 x 30 cm2. To reduce the interleaf transmission a 0.254-mm blocking step is included. End-leaf steps totaling 0.762 mm are also provided allowing opposing leaves to close off within the primary radiation beam. The neutron MLC also includes individual 45 degrees and 60 degrees automated universal tungsten wedges. The automated high-resolution neutron collimation provides an increase in patient throughput capacity, enables a new modality, intensity modulated neutron therapy, and limits occupational radiation exposure by providing remote operation from a shielded console area.

Measured microdosimetric spectra and therapeutic potential of boron neutron capture enhancement of 252Cf brachytherapy.

Californium-252 is a neutron-emitting radioisotope used as a brachytherapy source for radioresistant tumors. Presented here are microdosimetric spectra measured as a function of simulated site diameter and distance from applicator tube 252Cf sources. These spectra were measured using miniature tissue-equivalent proportional counters (TEPCs). An investigation of the clinical potential of boron neutron capture (BNC) enhancement of 252Cf brachytherapy is also provided. The absorbed dose from the BNC reaction was measured using a boron-loaded miniature TEPC. Measured neutron, photon and BNC absorbed dose components are provided as a function of distance from the source. In general, the absorbed dose results show good agreement with results from other measurement techniques. A concomitant boost to 252Cf brachytherapy may be provided through the use of the BNC reaction. The potential magnitude of this BNC enhancement increases with increasing distance from the source and is capable of providing a therapeutic gain greater than 30% at a distance of 5 cm from the source, assuming currently achievable boron concentrations.

Solid state microdosimetry in hadron therapy.

A report of recent developments in silicon microdosimetry is presented. SOI based microdosemeters have shown promise as a viable alternative to traditional tissue-equivalent proportional counters. The application of these silicon microdosemeters to such radiation therapy modalities as boron neutron capture therapy (BNCT), boron neutron capture synovectomy (BNCS), proton therapy (PT), and fast neutron therapy (FNT) has been performed. Several shortcomings of the current silicon microdosemeter were identified and will be taken into account in the design of a second-generation device.

Application of TEPC microdosimetry to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a bimodal radiation therapy used primarily for highly malignant gliomas. Tissue-equivalent proportional counter (TEPC) microdosimetry has proven an ideal dosimetry technique for BNCT, facilitating accurate separation of the photon and neutron absorbed dose components, assessment of radiation quality and measurement of the BNC dose. A miniature dual-TEPC system has been constructed to facilitate microdosimetry measurements with excellent spatial resolution in high-flux clinical neutron capture therapy beams. A 10B-loaded TEPC allows direct measurement of the secondary charged particle spectrum resulting from the BNC reaction. A matching TEPC fabricated from brain-tissue-equivalent plastic allows evaluation of secondary charged particle spectra from photon and neutron interactions in normal brain tissue. Microdosimetric measurements performed in clinical BNCT beams using these novel miniature TEPCs are presented, and the advantages of this technique for such applications are discussed.

Miniature tissue-equivalent proportional counters for BNCT and BNCEFNT dosimetry.

A dual miniature tissue-equivalent proportional counter (TEPC) system has been developed to facilitate microdosimetry for Boron Neutron Capture Therapy (BNCT). This system has been designed specifically to allow the analysis of the single event charged particle spectrum in phantom in high intensity BNCT beams and to provide this microdosimetric information with excellent spatial resolution. Paired A-150 and 10B-loaded A-150 TEPCs with 12.3 mm3 collecting volumes have been constructed. These TEPCs allow more accurate neutron dosimetry than current techniques, offer a direct measure of the boron neutron capture dose, and provide a framework for predicting the biological effectiveness of the absorbed dose. Design aspects and characterization of these detectors are reviewed, along with an exposition of the advantages of microdosimetry using these detectors over conventional dosimetry methods. In addition, the utility of this technique for boron neutron capture enhancement of fast neutron therapy (BNCEFNT) is discussed.

Attenuation and activation characteristics of steel and tungsten and the suitability of these materials for use in a fast neutron multileaf collimator.

A computer controlled multileaf collimator (MLC) is being designed to replace the multirod collimator (MRC) at present used to shape the d(48.5) + Be neutron beam from the Harper Hospital superconducting cyclotron. The computer controlled MLC will improve efficiency and allow for the future development of intensity modulated radiation therapy with neutrons. The existing MRC uses tungsten rods, while the new MLC will use steel as the leaf material. In the current study the attenuation and activation characteristics of steel are compared with those of tungsten to ensure that (a) the attenuation achieved in the MLC is at least equivalent to that of the existing MRC, and (b) that the activation of the steel will not result in a significant change in the activation levels within the treatment room. The latter point is important since personnel exposure (particularly to the radiation therapy technologists) from induced radioactivity must be minimized. Measurement of the neutron beam attenuation in a broad beam geometry showed that a 30 cm thick steel leaf yielded 2.5% transmission. This compared favorably with the 4% transmission obtained with the existing MRC. Irradiation of steel and tungsten samples at different depths in a 30 cm steel block indicated that the activation of steel should be no worse than that of tungsten.

Genistein potentiates the radiation effect on prostate carcinoma cells.

We have shown previously that genistein, the major isoflavone in soybean, inhibited the growth of human prostate cancer cells in vitro by affecting the cell cycle and inducing apoptosis. To augment the effect of radiation for prostate carcinoma, we have now tested the combination of genistein with photon and neutron radiation on prostate carcinoma cells in vitro. The effects of photon or neutron radiation alone or genistein alone or both combined were evaluated on DNA synthesis, cell growth, and cell ability to form colonies. We found that neutrons were more effective than photons for the killing of prostate carcinoma cells in vitro, resulting in a relative biological effectiveness of 2.6 when compared with photons. Genistein at 15 microM caused a significant inhibition in DNA synthesis, cell growth, and colony formation in the range of 40-60% and potentiated the effect of low doses of 200-300 cGy photon or 100-150 cGy neutron radiation. The effect of the combined treatment was more pronounced than with genistein or radiation alone. Our data indicate that genistein combined with radiation inhibits DNA synthesis, resulting in inhibition of cell division and growth. Genistein can augment the effect of neutrons at doses approximately 2-fold lower than photon doses required to observe the same efficacy. These studies suggest a potential of combining genistein with radiation for the treatment of localized prostate carcinoma.

Neutron or photon irradiation for prostate tumors: enhancement of cytokine therapy in a metastatic tumor model.

We have shown that implantation of human prostate carcinoma PC-3 cells in the prostates of nude mice led to the formation of prostate tumors with metastases to para-aortic lymph nodes. We found that day 6 prostate tumors were responsive to systemic injections of interleukin 2 (IL-2) therapy. We have now investigated the combination of primary tumor irradiation and IL-2 for metastatic prostate cancer in this preclinical tumor model. The effect of neutron radiation was compared with that of photon radiation. Advanced prostate tumors (approximately 0.4 cm) were irradiated, and a day later, mice were treated with systemic IL-2 for three weekly cycles. In separate experiments, mice were either sacrificed on day 30 to assess prostate tumor size and tumor histology or followed for survival. A dose-dependent inhibition of prostate tumor growth was caused either by photons or neutrons, but neutrons were more effective than photons with a relative biological effectiveness of 2. The tumor inhibition obtained with 250 cGy neutrons and 500 cGy photons was significant (>75%) and was further increased (> or = 90%) by addition of IL-2 therapy. In survival studies, the combination of radiation and IL-2 showed a significant survival advantage compared with untreated mice (P < or = 0.005) or radiation alone (P < or = 0.003) and an increase in median survival compared with IL-2 alone. Histologically, the combined regimen resulted in a greater degree of tumor destruction, inflammatory response, and vascular damage than that observed with each modality alone. After this combined treatment, no tumor was histologically detected in the para-aortic lymph nodes of these mice, and the lymph nodes were significantly smaller. These findings showed that primary tumor irradiation, either with neutrons or photons, enhanced IL-2 therapeutic effect for the treatment of advanced prostate cancer. This combined modality induced an antitumor response that controlled the growth of prostate tumors and their metastases.

A conducting plastic simulating brain tissue.

A new conducting plastic has been composed which accurately simulates the photon and neutron absorption properties of brain tissue. This tissue-equivalent (TE) plastic was formulated to match the hydrogen and nitrogen constituents recommended by ICRU Report #44 for brain tissue. Its development was initiated by the inability of muscle tissue-equivalent plastic to closely approximate brain tissue with respect to low-energy neutron interactions. This new plastic is particularly useful as an electrode in TE dosimetry devices for boron neutron capture therapy (BNCT), which utilizes low-energy neutrons for radiotherapy of the brain. Absorbed dose measurements in a clinical BNCT beam using a proportional counter constructed from this TE plastic show good agreement with Monte Carlo calculations.

Use of low-pressure tissue equivalent proportional counters for the dosimetry of neutron beams used in BNCT and BNCEFNT.

The absorbed dose in a phantom or patient in boron neutron capture therapy (BNCT) and boron neutron capture enhanced fast neutron therapy (BNCEFNT) is deposited by gamma rays, neutrons of a range of energies and the 10B reaction products. These dose components are commonly measured with paired (TE/Mg) ion chambers and foil activation technique. In the present work, we have investigated the use of paired tissue equivalent (TE) and TE+ l0B proportional counters as an alternate and complementary dosimetry technique for use in these neutron beams. We first describe various aspects of counter operation, uncertainties in dose measurement, and interpretation of the data. We then present measurements made in the following radiation fields: An epithermal beam at the University of Birmingham in the United Kingdom, a d(48.5) + Be fast neutron therapy beam at Harper Hospital in Detroit, and a 252Cf radiation field. In the epithermal beam, our measured gamma and neutron dose rates compare very well with the values calculated using Monte Carlo methods. The measured 10B dose rates show a systematic difference of approximately 35% when compared to the calculations. The measured neutron+gamma dose rates in the fast neutron beam are in good agreement with those measured using a calibrated A-150 TEP (tissue equivalent plastic) ion chamber. The measured 10B dose rates compare very well with those measured using other methods. In the 252Cf radiation field, the measured dose rates for all three components agree well with other Monte Carlo calculations and measurements. Based on these results, we conclude that the paired low-pressure proportional counters can be used to establish an independent technique of dose measurement in these radiation fields.

Paired Mg and Mg(B) ionization chambers for the measurement of boron neutron capture dose in neutron beams.

The use of the boron neutron capture (BNC) reaction to provide a dose enhancement in fast neutron therapy is currently under investigation at the Gershenson Radiation Oncology Center of Harper Hospital in Detroit, MI. The implementation of this treatment modality presents unique challenges in dosimetry. In addition to the measurement of photon and neutron doses in the mixed field, a measure of the thermal neutron flux and the associated boron neutron capture dose throughout the treatment volume is desired. A pair of small-volume magnesium ionization chambers has been constructed with the aim of providing this information. One of the chambers, denoted the Mg(B) chamber, is lined with a boron-loaded foil. The ionization response of this chamber has been calibrated in terms of BNC dose per ppm loading of 10B. These paired chambers can be used to map the local BNC response in neutron beams. From this data and an estimation of the boron concentration in the tumor and normal tissue, the boron neutron capture enhancement may be evaluated.

Responsiveness of human prostate carcinoma bone tumors to interleukin-2 therapy in a mouse xenograft tumor model.

We have tested an immunotherapy approach for the treatment of metastatic prostate carcinoma using a bone tumor model. Human PC-3 prostate carcinoma tumor cells were heterotransplanted into the femur cavity of athymic Balb/c nude mice. Tumor cells replaced marrow cells in the bone cavity, invaded adjacent bone and muscle tissues, and formed a palpable tumor at the hip joint. PC-3/IF cell lines, generated from bone tumors by serial in vivo passages, grew with faster kinetics in the femur and metastasized to inguinal lymph nodes. Established tumors were treated with systemic interleukin-2 (IL-2) injections. IL-2 significantly inhibited the formation of palpable tumors and prolonged mouse survival at nontoxic low doses. Histologically IL-2 caused vascular damage and infiltration of polymorphonuclear cells and lymphocytes in the tumor as well as necrotic areas with apoptotic cells. These findings suggest destruction of tumor cells by systemic IL-2 therapy and IL-2 responsiveness of prostate carcinoma bone tumors.

The cost-effectiveness of mixed beam neutron-photon radiation therapy in the treatment of adenocarcinoma of the prostate.

The results of clinical trials in the treatment of adenocarcinoma of the prostate using, mixed beam neutron/photon therapy, neutrons alone and photon therapy in combination with hormone treatment are compared. These trials indicate that neutron therapy is superior to photon/hormone therapy in achieving local control. The costs of delivering these two different therapies in a large US academic radiation oncology center at Wayne State University (WSU) are compared. The cost of a full course of mixed beam therapy is $20,142 compared to $18,871 for the photon/hormone treatment. Although the WSU neutron facility is a state-of-the-art installation, it is also a prototype device; it is estimated that a modern neutron facility based on this design would operate more cost effectively reducing the cost of a course of mixed beam therapy to $18,532.

Dosimetry of the boron neutron capture reaction for BNCT and BNCEFNT.

The use of paired proportional counters, constructed from A-150 tissue equivalent plastic (TEP) and A-150 TEP loaded with an appropriate amount of 10B (50 to 200 ppm), for the dosimetry of the boron neutron capture reaction has been investigated for several years at the Gershenson Radiation Oncology Center. This method has been used for determining the dose components (fast neutron, gamma ray and boron capture product dose) in both Boron Neutron Capture Therapy (BNCT) beams and in beams proposed for boron neutron capture enhancement of fast neutron therapy (BNCEFNT). A disadvantage of this method, when standard 1/2" diameter Rossi type proportional counters are used, is that the beam intensity must be relatively low in order to avoid saturation effects (pulse pile-up) in the counter. This is a major problem if measurements are to be made in a reactor beam, since reducing the beam intensity generally results in a change in the neutron spectrum. In order to overcome this problem, miniature cylindrical proportional counters have been developed which may be used in high intensity beams. The operational characteristics of these counters are compared with the standard 1/2" spherical counters. A further disadvantage of proportional counters is the relatively long time it takes to collect data, particularly if detailed information (depth-dose curves and beam profiles) is required. This problem could be overcome by using a set of ionization chambers (an A-150 TEP chamber, a Mg chamber and a Mg chamber with a 25 microns boron loaded inner wall) which can be scanned in a water phantom. After calibration against the paired proportional counters it should be possible to extract the fast neutron, gamma ray and boron neutron capture product doses from measurements made with these three ionization chambers. A set of such chambers has been used to make preliminary measurements in a fast neutron beam and the results of these measurements are presented.

Monte Carlo calculations to characterize the source for neutron therapy facilities.

Modern radiation treatment planning for photons includes full 3D modeling of the adsorbed dose distribution, accurate inclusion of the patient anatomy, and consideration of significant changes in material density and composition. Such efforts are founded in an accurate description of the radiation source and the beam delivery system. Modern fast neutron therapy facilities employ highly penetrating beams and isocentric beam delivery. Treatment planning is largely based on analytic models adapted from photon codes and interaction cross sections normalized to macroscopic attenuation. However, the recent PEREGRINE initiative at Lawrence Livermore Laboratory offers the possibility of fully stochastic modeling if the neutron source can be adequately described. In this article we report neutron source modeling of three high energy facilities. Neutron production is based on the intra-nuclear cascade model of the LAHET code while neutron transport through the beam delivery system is managed by MCNP using cross section libraries extended to 100 MeV neutron energy. PEREGRINE is then used to transport the neutron beam through typical phantoms. The resulting neutron sources are in excellent agreement with the limited experimental information and the measured phantom data are well described by the PEREGRINE transport using the LAHET/MCNP determined neutron sources.

Designing an optical distance indicator for a radiation therapy accelerator.

The computational aspects of the design of an optical distance indicator (ODI) for use with a radiation therapy accelerator are discussed. The specifics of the optical and mechanical design of an ODI for use with a superconducting cyclotron used for fast neutron therapy are presented.

Experimental determination of the thermal neutron flux around two different types of high intensity 252Cf sources.

The application of neutron emitting radioisotopes in brachytherapy facilitates the use of the higher biological effectiveness of neutrons compared to photons in treating some cancers. Different types of high intensity 252Cf sources are in use for the treatment of different cancers. To improve the therapy of bulky tumors the dose can be augmented by the additional use of the boron capture reaction of thermal neutrons. This requires information about the thermal neutron dose component around the Cf source. In this work, a Mg/Ar-ionization chamber internally coated with 10B was used to measure the thermal neutrons. These measurements were performed on two different 252Cf sources, one in use in the Gershenson Radiation Oncology Center at Harper Hospital in Detroit, MI, and one at the University Hospital of Chiang Mai in Chiang Mai, Thailand. The results of these measurements are compared and indicate that the differences in the construction of the sources influence the thermal dose component.

Direct determination of kerma for a d(48.5) + Be therapy beam.

An experimental determination of the neutron kerma ratio between muscle tissue and A-150 plastic was performed at the newly commissioned d(48.5)+ Be therapy facility in Detroit. Low-pressure proportional counters with separate walls made from A-150 plastic, graphite, zirconium oxide and zirconium served to measure ionization yield spectra. The absorbed dose in the wall of each counter was determined and rendered the A-150 and carbon kerma directly, whilst that for oxygen was deduced from differences between the matched metal oxide and metal pair. This enabled the evaluation of an effective kerma ratio as a function of radiation field size and hydrogenous filtration. Although filtration was observed to harden the beam, the application of a single kerma ratio for the various irradiation conditions investigated was found to be appropriate. A neutron kerma ratio of 0.90+/-0.03 was assessed for the Detroit facility, which is lower at the 1sigma level than the 0.95 currently recommended in the dosimetry protocol for high-energy neutron beams.