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.

Miniature semiconductor detectors for in vivo dosimetry.

Silicon mini-semiconductor detectors are found in wide applications for in vivo personal dosimetry and dosimetry and microdosimetry of different radiation oncology modalities. These applications are based on integral and spectroscopy modes of metal oxide semiconductor field effect transistor and silicon p-n junction detectors. The advantages and limitations of each are discussed.

Applicability of CORVUS pencil beam model and scatter dose model for intensity modulated neutron therapy.

Intensity modulated neutron radiotherapy (IMNRT) is currently being investigated as a mechanism to improve dose conformality in neutron radiotherapy, thereby minimizing normal tissue toxicity. This study investigates the applicability of two different dose calculation algorithms for IMNRT, a commercial system which utilizes a finite size pencil beam (FSPB) model, and an in-house planning system which uses a differential scatter air ratio (DSAR) method. Calculated dose distributions were compared with measured profiles for validation purposes. The beam-profiles matched to within +/-3% in the central region of the field. The 80-20% penumbra width as measured using an ionization chamber varied as 0.6 cm and 1.0 cm for 3 x 3 and 10 x 10 cm2 profile at a depth of 2.5 cm. The FSPB model fitted the data to a penumbra width of 0.1 cm for both 3 x 3 and 10 x 10 cm2 profiles. These results indicate that the commercial system needs further investigation. However, the in-house planning system has been validated for small irregular fields for IMNRT to an accuracy of +/-5%. Absolute dose measurements agreed with the calculated doses to within +/-3%.

Application of semiconductors for dosimetry of fast-neutron therapy beam.

Two types of ion implanted miniature p-i-n diodes were tested in a d(48.5) + Be fast-neutron beam produced in the Detroit superconducting cyclotron. The increase in forward voltage drop caused by neutron-induced damage was correlated with neutron dose measured in a water phantom. The neutron and gamma dose components were predetermined using twin detector (Tissue-equivalent ion chamber paired with miniature Geiger-Müller counter) method. The increase in the voltage drop for 1 mA injection current was monitored together with the cyclotron beam target current, thus the differential voltage drop could be defined precisely for given radiation dose. The average neutron sensitivities of tested diodes were 1.284 +/- 0.014 and 0.528 +/- 0.058 mV per cGy. The miniature detectors can be utilised in characterisation of small radiation fields and in the regions of high dose gradient as well as for in vivo dosimetry of the patients undergoing fast-neutron therapy.

Thermoluminescence dosimetry in mixed neutron/gamma radiation beam.

Miniature CaF2:Tm (TLD-300) were adopted for dosimetry in a mixed neutron/gamma beam produced by the Detroit superconducting cyclotron. A method utilizing the linear relationship between the ratios of the areas under the low and high temperature peaks of the glow curve and the ratios of gamma dose to total dose (Dgamma/DT) in d(48.5)+Be fast-neutron beam was applied for both the gamma component and the total dose measurements. The detectors were grouped based on their response to uniform 60Co dose. Within each group the ratio of the peak areas of the glow curve demonstrated uniformity and stability better than 1.5% (one standard deviation). The parameters of the linear regression between the fractional gamma component in the neutron beam and the ratio of peak areas were derived from measurements at locations with predetermined Dgamma/DT. The method was applied to measure the transmission through the existing multi-rod and newly designed multi-leaf collimators.

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.

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.

Neutron and photon clonogenic survival curves of two chemotherapy resistant human intermediate-grade non-Hodgkin lymphoma cell lines.

BACKGROUND: The potential role of neutron therapy in the management of intermediate-grade non-Hodgkin lymphoma (IGNHL) has not been examined because of the belief that the anticipated radiobiological effectiveness (RBE) would be uniformly very low. PURPOSE: To determine the fast neutron RBE for two chemotherapy-resistant IGNHL cell lines. METHODS AND MATERIALS: Conventional soft agar clonogenic survival curves following irradiation by 60Co and fast neutron were established for two IGNHL cell lines. These cell lines, WSU-DLCL2 and SK-DHL2B, were found in previous studies to be able to repair sublethal damage, and were also resistant to L-Pam and doxorubicin chemotherapy. RESULTS: When the surviving fraction after 2 Gy photon was chosen as the biological endpoint, the RBE for WSU-DLCL2 and SK-DHL2B measured 3.34 and 3.06. Similarly, when 10% survival was considered, the RBE for these two cell lines measured 2.54 and 2.59. The RBE, as measured by the ratios alpha neutron/alpha photon, for WSU-DLCL2, SK-DHL2B cell lines are 6.67 and 5.65, respectively. These results indicate that the RBE for these IGNHL cell lines is higher than the average RBE for cell lines of other histological types. CONCLUSION: Fast neutron irradiation may be of potential value in treating selected cases of IGNHL.

Radiobiological characterization of two human chemotherapy-resistant intermediate grade non-Hodgkin's lymphoma cell lines.

Intermediate grade non-Hodgkin's lymphoma (IGNHL) is generally considered a radiosensitive tumor that can be controlled with moderate radiation doses. Cell-survival curves of cell lines derived from IGNHL have been typically described to exhibit small or no shoulder, implying inability to accumulate or repair sublethal radiation damage. We characterize in this report the clonogenic radiation survival curves of two human IGNHL cell lines, WSU-DLCL2 and SK-DHL2B, established from patients who expired after having exhibited chemotherapy resistance of their tumors. The cells were irradiated with 60Co radiation at a dose rate of 85-100 cGy/min and cell survival data were analyzed according to the linear quadratic model. The alpha/beta values for WSU-DLCL2 and SK-DHL2B cells are 2 and 8.6, respectively. The corresponding SF2 are 0.42 and 0.35, respectively. Both cell lines are able to repair radiation-induced sublethal damage. These data indicate that these cells are only moderately radiosensitive.

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.

Measurement of the neutron sensitivity of TLD-300 irradiated in a tissue equivalent phantom by d(48.5) + Be neutrons.

The neutron sensitivities of the total response (kT) as well as of separate peaks 3 (k3) and 5 (k5) on the glow curve were measured for CaF2:Tm (TLD-300) thermoluminescent dosimeters. The TLD-300 were encapsulated in A-150 TE plastic and located at different depths in the water phantom. The phantom was irradiated with neutrons produced by the d(48.5) + Be reaction at the superconducting cyclotron of the Gershenson Radiation Oncology Center at Harper Hospital. A set of measurements, based on the use of a TE ionization chamber and Geiger-Müller (GM) counter was used to measure the neutron (Dn) and gamma (D gamma) dose at these locations. The neutron sensitivities of the TLDs were thus derived by comparison with the results obtained with the twin detector method. The average neutron sensitivities relative to gamma of the total response and the responses of single peaks 3 or 5 are 0.215 +/- 0.016, 0.126 +/- 0.010, and 0.357 +/- 0.014, respectively. A linear relationship was found between the ratio of the areas under peak 3 to that under peak 5 and the ratio of the gamma dose to the total dose.

Dose equivalents to neutron therapy facility staff due to induced activation.

The sources of the induced activity from the d(48.5)+Be fast neutron therapy beam of the Harper Hospital superconducting cyclotron have been investigated. The distribution of activity in the treatment room was measured, and the levels of dose equivalent to the staff were established. Activation spectra were measured with a high purity RE-Ge detector. Peaks corresponding to 28Al, 56Mn, 24Na, 64Cu, 66Cu, and 187W were present in the spectra. The dose equivalents due to the induced activation were measured by means of an ionization chamber type survey meter at six locations in the room. Irradiations of 120 monitor units were given at 15-min intervals, thus simulating the clinical situation. The measurements were made between the irradiations. The highest levels were registered around the treatment head. Two patterns are clearly distinguishable in these measurements. A fast decaying component with approximately 2 min half-life can be ascribed predominantly to 28Al and a slow growing component reaching saturation after about 4-5 treatments is associated with the presence of 56Mn. For uniform treatment load the activation build-up in each location was similar every day of the week with minimal values measured after the week end shut down. Personnel monitoring is achieved with dosimeters capable of detecting an extended range of neutron energies as well as beta rays and photons. Correlation between the number of fields treated and the doses to the radiation therapy technologists was shown. The mean dose equivalent received by the therapists is 7.1 +/- 0.2 microSv per treatment field. Means of reducing personnel dose equivalent levels are proposed.

A measurement of the fast-neutron sensitivity of a Geiger-Müller detector in the pulsed neutron beam from a superconducting cyclotron.

The kU value of a commercially available miniature energy compensated Geiger-Müller (GM) detector has been determined using the modified lead attenuation method of Hough. The measurements were made in a d(48.5)-Be neutron beam produced by the superconducting cyclotron based neutron therapy facility at Harper Hospital. The unique problems associated with making measurements in a 2 ms duration pulsed beam with a 20% duty cycle are discussed. The beam monitoring system, which allows the beam pulse shape at low beam intensities to be measured, is described. By gating the GM output with a discriminator pulse derived from the beam pulse shape, the gamma-ray count rates and dead-time corrections within the 2 ms pulse and between pulses can be measured separately. The kU value of (0.0245 +/- 0.0015) determined for this GM detector is consistent with the values measured by other workers with identical and similar detectors in neutron beams with comparable, but not identical, neutron spectra.

Hip stiffness following mixed conformal neutron and photon radiotherapy: a dose-volume relationship.

PURPOSE: To determine the relationship between dose, volume, and the incidence of hip stiffness in patients who received conformal neutron irradiation for prostate cancer. METHODS AND MATERIALS: A series of dose-searching studies using neutron irradiation for prostate cancer were performed to determine the optimal dose, fraction size, field size, technique, and proportions of photon and neutron dose. Neutron doses ranged from 9 to 20 Gy and photon doses ranged from 0 to 38 Gy. Data were analyzed by using a hip stiffness grading scale. RESULTS: Hip stiffness was recorded on follow-up examination in 30% of patients (40 out of 132) treated with fast neutrons or mixtures of fast neutron and photon radiation for prostate cancer. Hip stiffness was categorized as none (Grade 0, 92 patients), mild (Grade 1, 24 patients), moderate (Grade 2, 10 patients), or severe (Grade 3, 6 patients). The incidence of hip stiffness differed significantly by dose and volume in the five dose levels studied (p < 0.001). CONCLUSIONS: By using a mixture of conformal neutron and photon irradiation and limiting the total neutron dose to less than 13 Gy, hip stiffness toxicity could be reduced to acceptable levels.

Conformal mixed neutron and photon irradiation in localized and locally advanced prostate cancer: preliminary estimates of the therapeutic ratio.

PURPOSE: To determine the incidence of chronic toxicity and the probability of biochemical and histologic complete response among patients with nonmetastatic prostate cancer, treated with three dimensional (3D) conformal mixed neutron and photon irradiation. METHODS AND MATERIALS: Between November 1991 and December 1994, 151 patients with prostate cancer were entered in three prospective dose-finding studies of conformal mixed neutron and photon irradiation. Patients with low stage, low to intermediate grade prostate cancer (T1-2NXM0, Gleason Score < or = 7) received 38 Photon Gy (PhGy) plus 9 (51 patients) or 10 (53 patients) Neutron Gy (NGy) to the prostate and seminal vesicles. Forty-seven patients with locally advanced prostate cancer (T3-4 N0-1 M0 and/or Gleason Score > or = 8) received 15 NGy + 18 PhGy to the prostate and seminal vesicles and 9 NGy + 18 PhGy to the pelvic lymph nodes. RESULTS: The median follow-up was 16 months (range: 3-30 months). There was no Grade 3-5 GI or GU toxicity recorded. At 20 months, the actuarial rates of Grade 2 GI morbidity were 6 and 29% for the 9-10 and 15 NGy protocols, respectively (p = 0.07). At 20 months, the incidences of Grade 2 GU morbidity were 4 and 16%, respectively (p = 0.08). Stiffness in flexing or abducting the hips was seen in 20 and 42% of patients receiving 9-10 and 15 NGy, respectively (p = 0.01). Potency was maintained in 65% of all patients. Among patients with an initial PSA < or = 10, 100% had a 12-month PSA < 2 and 78% < 1 ng/ml. Negative postradiation biopsies were seen in 30% of patients 6 months, 79% at 12 months, and 84% of patients at 18 months. CONCLUSION: The use of conformal mixed neutron and photon irradiation has been well tolerated with no severe bladder or rectal complications observed. However, because of the enhanced toxicity seen with 15 NGy, the current maximum dose levels of neutron irradiation have been limited to 11 NGy.

RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities.

In fast neutron therapy, the relative biological effectiveness (RBE) of a given beam varies to a large extent with the neutron energy spectrum. This spectrum depends primarily on the energy of the incident particles and on the nuclear reaction used for neutron production. However, it also depends on other factors which are specific to the local facility, eg, target, collimation system, etc. Therefore direct radiobiological intercomparisons are justified. The present paper reports the results of an intercomparison performed at seven neutrontherapy centres: Orléans, France (p(34)+Be), Riyadh, Saudi Arabia (p(26)+Be), Ghent, Belgium (d(14.5)+Be), Faure, South Africa (p(66)+Be), Detroit, USA (d(48)+Be), Nice, France (p(65)+Be) and Louvain-la-Neuve, Belgium (p(65)+Be). The selected radiobiological system was intestinal crypt regeneration in mice after single fraction irradiation. The observed RBE values (ref cobalt-60 gamma-rays) were 1.79 +/- 0.10, 1.84 +/- 0.07, 2.24 +/- 0.11, 1.55 +/- 0.04, 1.51 +/- 0.03, 1.50 +/- 0.04 and 1.52 +/- 0.04, respectively. When machine availability permitted, additional factors were studied: two vs one fraction (Ghent, Louvain-la-Neuve), dose rate (Detroit), influence of depth in phantom (Faure, Detroit, Nice, Louvain-la-Neuve). In addition, at Orléans and Ghent, RBEs were also determined for LD50 at 6 days after selective abdominal irradiation and were found to be equal to the RBEs for crypt regeneration. The radiobiological intercomparisons were always combined with direct dosimetric intercomparisons and, when possible in some centres, with microdosimetric investigations.