Biological intercomparisons of neutron beams used for radiotherapy generated by p(+)-->Be in hospital-based cyclotrons.

The new generation of hospital-based neutron therapy facilities involve cyclotrons using protons on beryllium. The spectrum of neutrons produced includes a large and variable proportion of low-energy neutrons that are poorly penetrating but biologically effective. Cells cultured in vitro were used to compare the three US facilities at Seattle, M.D. Anderson and UCLA, together with the UK facility at Clatterbridge. Cyclotrons were compared within a given experiment on the same day using cells from a common suspension. Among the three US facilities, the relative potency factor at a depth of 25 mm differs by about 11%, with Seattle the least and UCLA the most biologically effective. Clatterbridge was compared directly with M.D. Anderson and found to be less effective by about 5%; it has a slightly lower biological effectiveness than any of the US facilities. There is evidence for an increased biological effectiveness in the build-up region, which reduces the effective skin sparing potential. There is not much difference in build-up between the three US facilities. Using the proton-on-beryllium neutron production process results in a wide spectrum of neutrons with a large but variable low-energy component. The biological effectiveness of the beam depends on target design and thickness as well as the design of the collimating system. Consequently the biological effectiveness of neutron beams generated by this process must be assessed on an individual basis. It cannot be assumed that because cyclotrons have similar accelerating energies that the relative biological effectiveness will be the same.     

Radiobiological intercomparison of two clinical neutron beams using the regeneration of mouse intestinal crypts

Determination of dose modification factor greatly facilitates the introduction of clinically proven neutron therapy schedules at new installations. We have compared the biological performance of the p(66)+Be neutron facility at Faure, South Africa, with the established p(65)+Be installation at Louvain-la-Neuve, Belgium. Filtration, D gamma/DT, dose rate and HVT 5/15 for the Louvain and Faure beam are: 2 cm, 2.5 cm polyethylene; 3%, 5%; 0.2 Gy/min, 0.4 Gy/min; and 20 cm and 19 cm respectively. Dosimetry was done in A-150 plastic. Irradiation of BALB/C mice was carried on according to the dose accumulation method in a perspex phantom at 5 cm depth and at an SSD of 150 cm at a field size of 28 X 28 cm2. Sections of the jejunum were prepared at each centre and analyzed by both. The RBE of the Faure beam determined at a survival level of 50 crypts ranged from 1.64 to 1.69. The dose modification factor RBE of the Louvain beam given by Beauduin et al. was 1.61 +/- 0.14. The dose modification factor of the Faure beam relative to the Louvain beam is thus 1.03 +/- 0.13 which could be expected from the similarity of the physical characteristics. Independent RBE measurements in a variety of systems also suggest similar biological properties. The depth variation of the RBE was found to be 4% (mouse gut) using 3 cm polyethylene filter over the depth range of 2.5 to 13.5 cm. This is in agreement with microdosimetry measurements using polyethylene filters of various thicknesses and with V79 measurements reported by Slabbert et al.     

The Clatterbridge high-energy neutron facility: dosimetry intercomparisons

Dosimetry intercomparisons have been performed between the Clatterbridge high-energy neutron facility and the following institutions, all employing beams with similar neutron energies: Université Catholique de Louvain, Belgium; University of Washington, Seattle, USA; MD Anderson Hospital, Houston, USA; and Fermi National Accelerator Laboratory, Batavia, USA. The purpose of the intercomparison was to provide a basis for the exchange of dose-response data and to facilitate the involvement of Clatterbridge in collaborative clinical trials. Tissue-equivalent ionization chambers were used by the participants in each intercomparison to compare measurements of total (neutron plus gamma) absorbed dose in the host institution's neutron beam, following calibration of the chambers in a reference photon beam. The effects of differences in exposure standards, chamber responses in the neutron beams and protocol-dependent dosimetry factors were all investigated. It was concluded that the overall difference in the measurement of absorbed dose relative to that determined by the Clatterbridge group was less than 2%.     

Present status of fast neutron therapy in Asian countries

The present status of the treatment with fast neutrons performed in Asian countries is reviewed and the experiences with respect to the radiobiological indications are presentated and discussed. There are three facilities under operation, the National Institute of Radiological Sciences (NIRS) in Chiba, the Institute of Medical Science (IMS) in Tokyo and the Korea Cancer Center Hospital (KCCH) in Seoul. The clinical experiences can be summarized as follows: Fast neutrons are the treatment of choice for carcinoma of the salivary gland, Pancoast tumor of the lung, osteosarcoma, soft tissue sarcoma and malignant melanoma. Provided the isodose planning can be improved, it seems that also squamous cell carcinoma of the head and neck and esophagus, adenocarcinoma of the lung, stage I and prostatic adenocarcinoma can be benefit from neutron therapy. The same holds for malignant meningioma, while the benefit for glioblastoma multiforme has not yet been confirmed. Studies are going on for the treatment of other cancers and for evaluating the possible role of neutron therapy in combination with surgery.     

Alternative irregular field collimation for fast neutron therapy

The neutron therapy program at the King Faisal Specialist Hospital and Research Centre was resumed in the spring of 1987. Due to the limited number of standard treatment cones, some form of beam modification was necessary. Originally we chose a cast iron blocking system, as adopted by other neutron treatment centers. For several reasons we found this arrangement to be generally unsatisfactory and inconvenient. We therefore, developed an alternative collimation system which resolved our earlier difficulties.     

Build-up and depth-dose characteristics of different fast neutron beams relevant for radiotherapy.

Build-up and central axis depth-dose curves have been obtained for d(50) + Be and d + T neutron beams. Measurements carried out with the collimator opening covered with a layer of lead showed that for all three neutron beams the entrance dose is approximately 60% of the dose at the maximum. Consequently the skin-sparing properties of these neutron beams will be approximately equal and comparable to those for electron beam therapy. Central axis depth-dose curves have been established for d(50) + Be neutrons at 129 cm SSD, for p(42) + Be neutrons at 125 cm SSD and d + T neurtons and 60Co gamma rays at 80 cm SSD. The 50% dose values in a water phantom are at depths of 12.7 cm, 12.0 cm, 9.7 cm and 12.7 cm respectively, for field sizes of approximately 15 cm x 20 cm. Insertion of a 6 cm thick nylon filter in the p(42)+Be beam increases this value from 12.0 cm to 13.5 cm. The gamma component for the d+T neutron beam is higher than for the cyclotron beams.     

An introduction to fast neutron therapy for the radiation therapy technologist

Clinical research into fast neutron radiation therapy has shown a renewed interest with the advent of the new generation cyclotrons presently being built and already on line in various parts of the country. These units will have neutron beams with better depth dose properties and uniform treatment policy for all facilities. This should ensure that adequate clinical studies are carried out that will define the role of fast neutron radiotherapy in the treatment of cancer.     

Review of clinical results of fast neutron therapy in the USA

Fast neutron radiotherapy in the United States is entering a new era in which dedicated hospital-based generators with isocentric beam capability are replacing treatment facilities based on fixed beams extracted from physics accelerators. All available clinical data, however, come from the older facilities. The majority of randomized trials conducted in the U.S. have used neutrons in a mixed schedule with photons, in which the aim was to deliver two-fifths of the total dose with neutrons; the neutron dose per fraction was set as the estimated equivalent of 2 Gy photons in terms of late normal tissue injury. Overall treatment time was held constant compared with the control photon therapy regimens (usually six to eight weeks). Random studies of this type showed no evidence of a therapeutic gain in the treatment of advanced primary carcinomas of the head and neck, lung, uterine cervix, or pancreas. A statistically significant benefit in favor of the mixed schedule is presently apparent for local control and survival in patients with advanced prostate cancer, and for clearance of neck nodes in patients with advanced squamous carcinoma of the head and neck. Based on encouraging results in a pilot study of mixed scheduled irradiation preoperatively for bladder cancer, a random study was begun in 1981, but too few cases have been accrued for analysis. Other randomized trials comparing protracted neutron only regimens with photon therapy have been conducted. These were negative for lung and pancreatic cancer, but a suggestion of a therapeutic gain (with small patient numbers) has been observed for treatment of inoperable salivary gland tumors and advanced squamous carcinomas of the head and neck. Two large randomized studies of various neutron doses delivered as a boost to high grade astrocytomas after or concurrently with photon irradiation have failed to define any therapeutic window between tumor destruction and brain necrosis. Based on a reassessment of all the available clinical and radiobiological data, and taking advantage of the greater technical flexibility offered by hospital-based facilities, the strategy of fast neutron therapy for future trials has been changed. In these trials neutrons are being used in a twelve fraction, four week regimen to treat gross disease, with elective therapy being given wherever possible using low LET irradiation. Concomitantly, research is proceeding to define predictors of tumor response to high LET radiations in order to better select patients for fast neutron radiotherapy.     

Radiobiological studies with therapeutic neutron beams generated by p+ leads to Be or d+ leads to Be

Mammalian cells cultured in vitro were used to study the radiobiological characteristics of neutron beams generated by 43 MeV protons on beryllium or 25 MeV deutrons on beryllium. For an unfiltered beam of neutrons generated by 43 MeV p+ leads to Be the relative biological effectiveness was found to be 8-12% higher at a depth of 2 cm than at a depth of 12 cm due to the presence of a large component of low-energy neutrons. The addition of a hydrogenous filter 4 cm thick preferentially removed the low-energy neutrons from the beam and, as a result, the neutron RBE was independent of depth. There was no significant difference in the oxygen enhancement ratio between the filtered neutrons produced by 43 Mev p+ leads to Be and neutrons produced by 25 MeV d+ leads to Be; for both beams the OER value was about 1.6.