This report presents the design and testing of an external target system for clinical‐scale production of 211At on the Scanditronix MC‐50 cyclotron at the University of Washington Medical Center. While other 211At production sites have typically employed an internal target, an external target setup was deemed necessary at our facility since the cyclotron's main application is for cancer patient treatment via fast neutron therapy. The challenge was that previous external 211At targets demonstrated reduced yields when compared to internal target systems. The target developed in this study has been used in more than 100 irradiations. From those irradiations 211At saturated yields of 181 ± 16 MBq/μA and 241 ± 17 MBq/μA at 28.0 and 29.0 MeV, respectively, were obtained. Importantly, consistent yields were observed over the 25–60 μA range of irradiation currents evaluated. With a recent production in excess of 4 GBq 211At for a 29.0 MeV, 58 μA, 4‐hour irradiation, this external target system has demonstrated its potential for producing clinically relevant quantities of 211At.

The clinical cyclotron facility in Seattle is one of just a few centers world-wide treating cancer patients with fast neutrons. This treatment remains the treatment of choice for advanced salivary gland tumors and is effective on some other tumors as well. In addition the cyclotron is used for production of specialty radionuclides and occasional other irradiations. Many parts of the facility have been systematically upgraded over the years and a major effort is underway to replace the outdated control system. The first components of this system are now operational. It is EPICS-based and is running on multiple Linux computers connected by a private network. Control of devices such as power supplies is via TCP/IP over Ethernet and gateway connections to GPIB and RS232, or via Modbus TCP/IP. As longer shutdowns are unacceptable for a clinical application the new system is introduced in stages with the old and new system each running parts of the facility.

The dependence of the wedge factors (WFs) on field size (FS) and depth for a fast neutron beam has been investigated. In a previous study (Popescu et al 1999 Med. Phys. 26 541), a method was presented that allows a simple and accurate way of calculating the wedge-factor dependence on FS and depth in the case of a photon beam. The validity of a similar approach is tested in the present study for neutron beam dosimetry. The clinical neutron therapy system at the University of Washington (UW) has a flattening filter assembly consisting of two filters: a small field filter and a large field filter. Despite this complication, the approach presented in Popescu et al (1999 Med. Phys. 26 541) can be used to describe the WF dependence on FS and depth (d).

An investigation has been conducted to assess the in vivo stability of a series of astatinated benzamides and astatinated nido-carborane compounds in mice. It was hypothesized that the higher bond strength of boron-astatine bonds in the nido-carboranes might provide increased stability toward in vivo deastatination. Four tri-n-butylstannylbenzamides were prepared for radiohalogenation and evaluation in vivo. Those compounds were N-propyl-4-(tri-n-butylstannyl)benzamide 1a, N-propyl-3-(tri-n-butylstannyl)benzamide 2a, ethyl 4-tri-n-butylstannylhippurate 3a, and 4-tri-n-butylstannyl-hippuric acid 4a. Seven mono-nido-carboranyl derivatives were prepared for radiohalogenation and in vivo evaluation. Four of the seven mono-carboranyl derivatives (5a, 6a, 7a, 13a) contained a 3-(nido-carboranyl)propionamide functionality, and the remaining compounds (8a, 8g, 10a) contained a 4-(nido-carboranyl)aniline functionality. Two additional derivatives (11a, 12a) were prepared that contained bis-(nido-carboranylmethyl)benzene moieties (also referred to as Venus flytrap complexes (VFCs). All benzamide and nido-carborane compounds underwent facile iodination and radiohalogenation, except a 4-(nido-carboranyl)aniline derivative, 8a. Iodination of 8a resulted in a mixture, of which the desired iodinated product was a minor component. Therefore, radiohalogenation was not attempted. It is believed that the mixture of products is due to the presence of a thiourea bond. Previous studies have shown that thiourea bonds can interfere with halogenation reactions. In vivo comparisons of the compounds were conducted by co-injection of dual labeled (125/131I and 211At) compounds. Tissue distribution data were obtained at 1 and 4 h postinjection of the radiolabeled compounds, as that was sufficient to determine if astatine was being released. Stability of the astatinated compound was assessed by the difference in concentration of radioiodine and astatine in lung and spleen. All of the benzamides were found to undergo rapid deastatination in vivo. The nido-carborane derivatives appeared to be slightly more stable to in vivo deastatination; however, they had long blood residence times. The surprising finding was that the VFC derivatives did not release 211At in vivo, even though they rapidly localized to liver. This finding provides encouragement that stable conjugates of 211At may be attained if appropriate modifications of the VFC can be made to redirect their excretion through the renal system.

This is the therapist’s guide for the control of the isocentric treatment unit at the Clinical Neutron Therapy System (CNTS) at the University of Washington Medical Center. This guide provides instructions for performing typical treatment procedures. A separate reference manual provides detailed descriptions of each key, display, message, etc. This guide only describes the features of CNTS that are needed to perform treatments and which are the therapist’s responsibility. Other manuals describe the features that support troubleshooting and recovering from problems, calibration, physics, and engineering.

This reportdescribesa new computercontrolsystemfor a radiationtherapy machinewith an isocentricgantryanda multileaf collimator. It discussesthe motivation andrationalefor someof the featuresanddevelopmentactivities, andreportsseveralmeasuresof development effort, performance, andquality, determinedafteralmosttwo yearsof operatingexperience. Notable featuresof the control systeminclude constructionbasedon standard(vendorindependent) hardwareandsoftwarecomponentsconnectedbyanetwork,asimpleandefficient userinterface,closeintegrationwith thetreatmentplanningsystem,automatedrecordkeeping for patientqualityassuranceandmachinemaintenance, andeaseof maintenanceandupgrading. Separationof control functionsfrom datamanagement functionsresultsin a control program which is small,fast,andfeasibleto analyzethoroughly. Choiceof featuresandinternaldesign wereinformedby fifteenyearsexperienceusingandmaintainingcomputercontrolledtherapy machines. Thedevelopmentmethodwaschosento ensureexceptionalsafety, reliability, andclinical acceptability. Much of thedetailedspecificationwasexpressedin formal (mathematical)notation. This formal specification(not theprosedescription)servedasthebasisfor mostcoding, testplanning,andsafetyanalysis.Testingandreviews weresupplementedby new automated analysesmethodsincluding theoremprovingandmodelchecking.

Fast neutron radiotherapy utilizes neutrons in the energy range of several millions to several tens of millions of eV to treat human malignancies. These fast neutron beams produce a small cloud of "slow" neutrons as they penetrate the body. If one can selectively attach isotopes having large neutron capture cross sections (such as B-10) to cancer cells, these "slow" neutrons can be used to enhance the killing of tumors. We describe a multidisciplinary effort to apply this technique to the treatment of patients with inoperable, non-small cell lung cancers. Problems in target design, compound development, beam optimization, and radiobiological experiments are discussed.

The clinical cyclotron facility in Seattle continues to provide beams for neutron therapy and PET isotope production. Over 2000 patients have so far been treated using an isocentric gantry with multi-leaf collimator. Downtime remains below 2%. A new therapy control system has been in operation for nearly two years now and works efficiently and reliably. Developments to extend the therapeutic window for neutron therapy by adding a boron neutron capture dose component selectively to the tumor are continuing. Several beryllium-tungsten target combinations have been investigated with regard to neutron spectrum, dosimetry and radiobiology. The project of an external ion source to increase flexibility to accelerate other particle beam, in particular He-4(++) has been abandoned. The change-over to such a system would have created too serious an interruption in the therapy schedule. Instead, modifications to the existing internal cold cathode pig source are being investigated. Substantial progress has been made and the goal of 50 muA at an external target station appears achievable.

Stimulated by requests by users to run high current alpha beams for isotope production, the University of Washington has requested that TRIUMF perform a design study of an axial injection system. The goals of the study include finding a relatively simple retrofit for the MC50 that will add the alpha beam capability while maintaining or improving the operation for proton and deuteron beams currently used. It must also be possible to install the new system with little or no disruption of the normal operation that includes regular neutron therapy treatments. In this paper the results of the study will be presented.

The fast neutron therapy facility in Seattle is based on a cyclotron, which produces a 50.5 MeV proton beam. Neutrons are produced in a beryllium target installed in an isocentric gantry equipped with a multi-leaf collimator. The system has been in routine operation for 14 years and over 1800 patients have been treated. Downtime has been minimal, over the past 10 years less than 1.5% of the scheduled daily treatment sessions could not be delivered for equipment related reasons. Fast neutron therapy has been shown to be highly effective for the treatment of salivary gland tumors, sarcomas of bone and soft tissues and for certain prostate cancers. In addition there are situations such as non-small cell lung cancer, where results are promising, but success is limited by normal tissue complications. A relatively small selective increase in the tumor dose might lead to a significant clinical improvement in these situations. The use of a boron neutron capture (BNC) boost, utilizing the moderated slow neutrons n...

The clinical cyclotron facility in Seattle continues its operation with traditional fast neutron therapy and production of PET isotopes. System availability remains high. Improvements to the extraction efficiency resulted in an increased beam intensity and a 3.5 kW beam is now routinely used for neutron production with the beryllium target in the therapy head. Neutron spectrum measurements have been performed using foil activation techniques. These measurements are part of the effort to enhance fast neutron therapy by baron neutron capture of moderated slow neutrons in the patient. Dosimetric measurements and animal experiments ate being conducted for this modality. Improvements were made to the control system, power supplies and the neutron collimation system, where radiation damaged components had to be replaced. Plans for an external ion source for improved operation with different particle beams for production of experimental medical radionuclides are actively pursued.

Clinical trials have revealed a therapeutic advantage for fast neutron radiation over conventional photon radiation for salivary gland cancer, prostate cancer, sarcoma, and a subgroup of lung cancer. Conversely, fast neutron treatment of high grade astrocytic brain tumors [glioblastoma multiforme (GBM)] resulted in tumor sterilization, but also caused significant brain injury such that no therapeutic gain was attained. This effect was important, however, in that photon radiation and other conventional treatments have not demonstrated sterilization of GEM at any dose. Recent laboratory studies demonstrated that the hospital-based fast neutron beam from the University of Washington cyclotron has a thermal neutron component that may be used in a boron-10 neutron capture (BNC) reaction to enhance cell kill. The degree of enhancement was approximately 10 fold, and was dependent upon the boron-10 concentration, the boron-10 carrier agent, and the fast neutron dose per fraction. The results of these experiments will be discussed in the context of creating a therapeutic window for treatment of glioblastoma using BNC-enhanced East neutron radiation in a clinically tolerable regimen.

At therapeutic doses fast neutron radiotherapy alone gives significant tumor control can result in a significant increase in tumor control probability. As a fast neutron beam penetrates tissue it is partially moderated producing a cloud of thermalized neutrons. We describe measurements of this thermalized component using the therapy beam at the University of Washington and show how it is possible to increase its magnitude without appreciable degradation of the other clinical properties of the beam. We describe model calculation of the radiobiological effects of a boron neutron capture boost as well as in vitro cell culture measurements on the V-79 cell line, in vivo experiments on the 36B10 rat glioma system, and a preliminary experiment on a human melanoma nodule test system. Plans to extend this work to clinically-relevant tumor systems are discussed.

Purpose: We have investigated the requirements, design, implementation, and operation of a computer-controlled medical accelerator with multileaf collimator (MLC), integrated with a radiation treatment-planning system (RTPS), and we report on the performance, benefits, and lessons learned from this experience.Methods and Materials: In 1984 the University of Washington installed a computer-controlled radiation therapy machine (the Clinical Neutron Therapy System, or CNTS) with a multileaf collimator. Since the beginning of operation the control system computer has been connected by commercially available network hardware and software to three generations of radiation treatment-planning systems. Semiautomated setup and completely computerized check and confirm were incorporated into the system from the beginning of clinical operation in 1984. The system cannot deliver a patient treatment without a computer-prepared treatment plan.Results: The CNTS has been in use for routine patient treatments for over 11 years. The cost of the network connection and software was an insignificant fraction of the facility cost. Operation has been efficient and reliable. Of the 441 machine-related session reschedulings (out of 18,432 sessions total) during the past 9 years, only 20 were due to problems with data transfer between the RTPS and CNTS, associated primarily with two incidents. Close integration with the treatment-planning system allows complex treatments to be delivered. Dramatic evolution of the departmental treatment-planning system has not required any changes or redesign of either the accelerator control system or the network connection.Conclusions: Our experience shows that a large degree of automation is possible with reasonable effort, by using well-known software and hardware design strategies. The lessons we have learned from this can be carried over into photon therapy now that photon accelerators with MLC facilities are commercially available. (C) 1997 Elsevier Science Inc.

Fast neutron radiotherapy has proven to be an effective form of treatment in a selected subset of tumors (salivary gland tumors, sarcomas, and locally-advanced prostate cancer), but has not proven to be more beneficial than conventional photon irradiation for the majority of tumor types upon which it has been tested. Normal tissue tolerance limits preclude simply further escalating the neutron dose. Boron neutron capture (BNC) provides a way of selectively augmenting the radiation dose to the tumor. This process is described, and cell culture and animal model data reviewed. An irradiation configuration was developed where an enhancement of 2.10(-3) for 1 microgram of 10B per gram of tissue was achieved. This is similar to the enhancement achievable in the center of a 20 x 20 cm field envisioned for future applications such as metastases in the brain. A boron concentration of 50 micrograms per gram of tumor tissue leads to a 10% increase in the delivered physical dose in this scenario. The first human test of BNC enhancement of a fast neutron radiotherapy beam using pharmacologically-acceptable doses of orally-administered, 10B-enriched, L-paraboronophenylalanine is reported. An enhancement of tumor response was demonstrated for a melanoma skin nodule test system. Boron levels achieved in blood, skin, and tumors are presented. Future research plans are discussed.

PURPOSE:Fast-neutron irradiation and boron-neutron capture therapy (BNCT) have been independently investigated as treatments for malignant disease. This study tested the feasibility of enhancing fast-neutron irradiation with concomitant BNCT.MATERIALS AND METHODS:Seventeen male Fisher rats, each weighing 180-200 g and bearing 36B10 gliomas, were irradiated with graded doses of fast-neutron radiation. Half of the animals received an L-para-boronophenylalanine (BPA) fructose complex prior to treatment. An in vitro colony-forming assay was used to measure surviving fraction.RESULTS:A significantly lower surviving fraction was noted in the tumors from the BPA group compared with those receiving neutrons alone at the three lower neutron doses (P < .005). With use of a linear quadratic curve fit of cell survival, the dose modifying factor was 1.32 at the 0.10 surviving fraction. Mean tumor boron concentration was 68.4 micrograms/g.CONCLUSIONS:BNCT enhancement of fast-neutron irradiation is feasible in an in vivo tumor system.

Purpose: For many years neutron radiation has been used to treat malignant disease both as fast neutron radiotherapy and as thermal neutron induced boron neutron capture therapy (BNCT). To date, these two approaches have been used independently of one another due to the large difference in neutron energies each employs. In this paper we discuss the potential application of BNCT to enhance the therapeutic effectiveness of a fast neutron radiotherapy beam.Methods and Materials: Measurements are presented for the thermal neutron component that is spontaneously developed as the University of Washington fast neutron radiotherapy beam penetrates a water phantom. The biological effect of this thermalized component on cells ''tagged'' with boron-10 (B-10) is modeled mathematically and the expected change in cell survival calculated. The model is then extended to estimate the effect this enhanced cell killing would have for increased tumor control.Results: The basic predictions of the model on changes in cell survival are verified with in vitro measurements using the V-79 cell line. An additional factor of 10-100 in tumor cell killing appears achievable with currently available B-10 carriers using our present neutron beam. A Poisson model is then used to estimate the change in tumor control this enhanced cell killing would produce in various clinical situations and the effect is sufficiently large so as to be clinically relevant. It is also demonstrated that the magnitude of the thermalized component can be increased by a factor of 2-3 with relatively simple changes in the beam generating conditions.Conclusion: BNCT may provide a means of enhancing the therapeutic effectiveness of fast neutron radiothearapy in a wide variety of clinical situations and is an area of research that should be aggressively pursued.