The proton treatment center at Loma Linda University Medical Center: Rationale for and description of its development

In,. J. Radiation Oncology Bid. Phys. Vol. 22. pp. 383-389 Printed m the U S.A. All nghts reserved.

Copyright

03KJ-3016/92 $5.00 + .I0 B 1991 Pergamon Press plc

??History and Heritage

THE PROTON TREATMENT CENTER AT LOMA LINDA UNIVERSITY MEDICAL CENTER: RATIONALE FOR AND DESCRIPTION OF ITS DEVELOPMENT JAMES M. SLATER, M.D.,

FACR, JOHN 0. ARCHAMBEAU,M.D., DANIEL W. MILLER, PH.D., MICHAEL I. NOTARUS, WILLIAM PRESTON, ED.D., AND JERRY D. SLATER, M.D. Department

of Radiation Medicine,

Loma Linda University

Medical Center, Loma Linda, CA

Proton radiation, a continuation of radiation oncology’s historic search for an optimum dose distribution, offers superior characteristics for clinical radiation therapy. A complete facility for clinical proton radiation therapy has been designed for and constructed at Loma Linda University Medical Center. To bring about this achievement, a consortium of engineers, physicists, and physicians interested in the clinical applications of protons was necessary. The accelerator, the beam transport and delivery systems, the building, and the personnel who operate the system were ail brought together to fully exploit the properties of protons for patient treatments, which are now underway. Accelerators, Charged particles, Deslgn and development, Protons, Radiotherapy.

introduction of more effective local therapy” (36). The classic intent of radiation oncology is to deliver ionizing radiation only to diseased tissue (9). In practice, this ideal is compromised: Normal tissue is always included in radiation fields. The tolerance of the normal issue in those fields often determines the dose the radiation oncologist can deliver; the resulting dose is frequently insufficient to control the cancer. Radiation oncologists seek as low a rate of side effects and complications as possible, consistent with maximum locoregional cancer control. Complications can include disfigurement, dysfunction, disability, and even death. Improving the precision with which the radiation dose can be delivered and even increased to the designated volume, while avoiding undesignated tissues, should reduce complications or side effects, a goal of all practicing radiation oncologists.

INTRODUCTION

A serious need exists to improve local cancer control. An equally serious need exists to improve quality of life for the cancer patient through the anatomic and functional preservation of tissues and organs. In spite of current methods employed to the best capabilities of oncologists, however, failure to control local disease still occurs annually in approximately 225,000 persons in the United States (10). A window of opportunity exists between the time a solid tumor begins to form and regional and/or distant metastases occur. Within this window, local treatments must work effectively. If they do, controlling the disease is equivalent to curing the patient, as evidenced by the patients whose cancers are permanently controlled by local or locoregional treatment alone. The importance of locoregional control, and the reduction of treatment morbidity, are the fundamental reasons why the enormous task of developing a hospital-based proton treatment center was undertaken.

Prerequisites for precision therapy

It has been estimated that 70% of cancer patients will have micrometastases beyond the primary site, at initial presentation (27). The 30% who have localized cancer, at current estimates of new cancer cases, represent over 300,000 patients presenting annually with localized cancer (30). For such patients, as Suit and Miralbell observe, “the history of oncology shows major gains in survival with the

As the capability for improved precision of radiation delivery increases, so too does the risk of missing the full extent of the tumor target. Two basic technologies must be included in radiation oncologists’ daily activities to minimize this risk: a) defining the designated volume with superb care and b) positioning the patient with equal care. This implies the need for a total therapy system that includes patient registration so that the designated volume may be accurately and reproducibly treated. Employing such technologies enables radiation oncologists to take maximum advantage of precision dose delivery systems,

Reprint requests to: James M. Slater, M.D., Chairman, Dept. of Radiation Medicine, Loma Linda University Medical Center,

11234 Anderson St., Box 2000, Loma Linda, CA 92354. Accepted for publication 10 October 1991.

Improving locoregional disease control and reducing morbid@

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the most precise of which is charged-particle radiation therapy. As we approach the limits of conformal radiation using photons and electrons, heavy charged particles provide a new dimension for radiation oncologists, further improving their ability to place radiation precisely within the delineated volume. Computer simulations comparing photon beam with proton beam distributions are shown elsewhere in this issue. Either beam can be optimized; however, the superior distribution of the proton beam is clearly evident. PROTONS:

RATIONALE

FOR THEIR

USE

Protons were selected as the particle of choice for the Loma Linda University Medical Center (LLUMC) facility because: a) they have favorable absorption characteristics in tissues, rendering them superior to photons and electrons for clinical radiation therapy; b) their radiobiologic characteristics are similar to photons and thus are wellknown; and c) given the current status of accelerator technology, the cost of delivering protons is relatively low compared to heavier charged particles. Protons’ favorable absorption characteristics result from their charge and heavy mass, 1,835 times that of an electron. These factors provide the basis for predicting and controlling their depth of travel within the patient. The protons’ energy upon entering the patient, and the tissue density along their track, determine the depth of penetration of the beam and placement of the Bragg peak. This peak can be spread out to conform to the thickness of the designated volume along the beam axis. The heavy mass also results in minimal deviation and, therefore, minimal side-scatter. Protons interact primarily by ionization, as do photons and electrons. Only about 2% of their energy is deposited through nuclear interactions; hence, their RBE is similar to photons and their therapeutic advantage rests with the suprior controllability of the beam (2). Photons and electrons lose most of their energy near the body’s surface, exponentially deposit energy as they travel through tissue, and are associated with significant secondary lateral scatter. Normal tissues surrounding the target frequently receive higher doses than the designated volume, from each single port. Attempting to circumvent these problems, radiation oncologists often employ multifield arrangements. Protons, however, offer a means of depositing the maximum energy within the designated volume from each single port, thus minimizing normal-tissue effects. As a result of protons’ dose-distribution characteristics, the radiation oncologist can increase the dose to the tumor while reducing the dose to surrounding normal tissues. This allows the dose to be increased beyond that which less conformal radiation will allow. The ultimate results of this treatment remain to be determined; many studies have been underway since protons were first used clinically and many more are being planned now.

Volume 22, Number 2, 1992

HISTORICAL

MILIEU

OF PROTON

THERAPY

Proton irradiation evolved from earlier attempts to maximize radiation effects to designated volumes while minimizing or eliminating radiation damage to adjacent healthy tissue. Such earlier attempts included dose fractionation to take advantage of the relatively greater recovery potential of normal tissues (15), and various methods of improving dose distributions, such as multifield treatment arrangements, intracavitary and interstitial therapy (25), increasing the energy of linear accelerators to reach deep tumors (6, 8, 15), and employing particle beam therapy to take advantage of increased RBE or dose distribution (8, 24, 37). The first proposal to employ proton beams generated by high-energy physics research accelerators, for medical purposes, occurred in 1946 (41). By 1954, proton beams were first used for humans at Lawrence Berkeley Laboratory (LBL); 26 patients received pituitary irradiation for advanced breast cancer (38, 39). The second application of a physics research accelerator for proton therapy occurred in Sweden in 1957; by 1968, 69 patients had been treated and research has continued thereafter (11, 12, 19, 20). Physicians working with Harvard Cyclotron Laboratory (HCL) began employing a 160-million-electron-volt (MeV) proton beam for therapy in 1959; pituitary adenomas were first treated in 1963 (16, 17), followed by other malignant tumors in 1973. Large-field radiation therapy began at Harvard in 1974, as the applications of the superior physical dose distribution of the proton beam to a broad range of tumors became apparent (33-35). Proton beam therapy began at Dubna, USSR, in 1967; subsequently, other facilities were built at Moscow in 1969 and Gatchina in 1973 ( 1). The Japanese experience began in 1979, at Chiba; another facility opened at Tsukuba in 1983 (40). At the Paul Scherrer Institute, formerly the Swiss Institute for Nuclear Research (Villigen, Switzerland), proton beam therapy commenced in 1985 (7). Currently, over 9,200 patients have been treated with protons in these and other institutions around the world (26). Results achieved with difficult-to-treat tumors show the benefits of proton irradiation. Some ophthalmologists treat ocular melanomas, for example, by enucleation. Where proton therapy or qualitatively similar helium ion therapy have been used, however, the control rate is more than 95%, and most patients retain useful vision in treated eyes (3, 13, 14, 22, 23, 28). Pituitary tumors show similar results and, like small tumors of the eye, can in some cases be treated in one to three days on an outpatient basis (5, 21). Chondrosarcomas of the base of the skull are difficult to control because of their proximity to the brain stem. Proton and helium ion therapy, however, have yielded control rates of approximately 85% (4, 29, 35). Proton therapy has also been successfully employed in some noncancerous disease processes, such as arteriovenous malformations of the brain (32). Although the precision of proton therapy has been known for decades, applications have been limited to a few

LLU proton treatment center 0 JAMESM. SLATER et al.

anatomic sites because physics research accelerators were not designed for treating patients, and because many tumors could not be localized with sufficient precision. One could not justify building a proton delivery system capable of extending the benefits of precision proton therapy to all anatomic sites, if the tumors in those sites could not be defined with equal precision. In the late 1970’s and through the 1980’s, however, CT, MRI, SPECT, PET, ultrasound, improved conventional imaging modalities, and improved means of contrast enhancement, all increased the precision with which disease extent is defined. These improvements, combined with better understanding of tumor biology and the radiobiological effects of conventional and heavycharged-particle irradiations, justified the expense and effort required to build a proton accelerator and facility designed for patient treatments, such as has occurred at LLUMC

DESIGNING AND BUILDING THE LOMA LINDA FACILITY Stirrings of interest

In the winter of 1984, two of us (Archambeau and Slater) visited Argonne National Laboratory to discuss options for developing proton accelerators. That same year, Herman Suit, M.D., of HCL and Massachusetts General Hospital (MGH), who was also pursuing his interests in proton therapy, met with Slater at the ASTRO meetings in Washington, D.C. to consider some kind of joint effort. These discussions, and others which were ongoing among a number of individuals and institutions interested in the therapeutic applications of protons, led to the idea of a consortium to help with the planning process. It was clear that enormous complexities would be involved in developing such a program. It was decided, therefore, that a meeting of representatives from the high-energy physics laboratories, and other persons who had shown interest in heavy-charged-particle therapy, would be held at Fermi National Accelerator Laboratory (Fermilab) in January, 1985. From a small number of physicians, physicists, and engineers interested in developing charged-particle treatment capabilities came the working group that would meet together at regular intervals for the purpose of defining the design requirements for the accelerator, beam transport system, beam delivery sysem, and the facilitity to house this hardware. The consortium became known as the Proton Therapy Cooperative Group, or PTCOG. Herman Suit was the first chairman of the PTCOG Steering Commitee; Michael Goitein, Ph.D. (HCL and MGH), served as the group’s first secretary. The other members of the Steering Committee were: John Archambeau, M.D. (Loma Linda); Joseph Castro, M.D., and Richard Gough, Ph. D. (LBL); Stanley Schriber, Ph.D., Los Alamos National Laboratory (LANL); James Slater, and Richard Wilson, Ph.D. (HCL). The initial PTCOG meeting was held in one of the Fermilab directors’ conference rooms. Scientists from around the world, coming together at their own initiative and

385

expense, met to begin discussing the requirements for designing a medical proton therapy facility. Ninety-three scientists attended the two-day meeting; most of them, and others who have joined the effort since, have continued to meet at 6-month intervals. No outside funding has occurred and each attendee or the attendee’s home facility has covered all expenses, suggesting an unusual degree of dedication to the program. The group divided its tasks into three major areas of interest and formed three subcommittees to investigate them: a) accelerator design, cochaired by Stanley Schriber and Richard Gough; b) facility design, cochaired by James Slater and Richard Wilson; and c) clinical studies, cochaired by John Archambeau and Joseph Castro. Committee meetings were (and are) characterized by free and stimulating scientific interchange. It soon became evident that several basic questions needed to be answered. For example, what kind of particle should be employed? Protons? if so, positive or negative? If not protons, what? Helium ions? Heavier charged particles? What kind of accelerator should be developed to most fully exploit the capabilities of the particle and apply it to the medical environment? A linear accelerator? A cyclotron or synchrotron? Many discussions, some of them heated by the fires of deep convictions, ensued over such fundamental questions. As time passed, the design requirements for the accelerator, the beam transport system, the treatment room delivery system, and the facility layout itself began to take shape and to assume sufficient form that the feasibility for developing an engineering design became evident. In January, 1986, therefore, we approached Philip Livdahl, Deputy Director of Fermilab, to popose that Fermilab develop the engineering design of the accelerator and its beam transport system for Loma Linda University. Mr. Livdahl passed the proposal on to Fermilab’s Administration, ultimately to its Director, Leon Lederman, Ph.D., who supported it. The proposal subsequently was reviewed by the U.S. Department of Energy (DOE), owners of Fermilab, and by the University Research Association (URA), operators of Fermilab, where it was again received favorably. Design and development Unique requirements. The requirements for a medically-

dedicated proton accelerator are different than those for a physics research machine (31). Not only must beam energy be variable, permitting varying depths of penetration, but the beam must be extremely well-controlled for intensity, homogeneity, energy, and cross-sectional size, shape and position, to allow for precise conformal treatments. The fundamental requirements, calling for an accelerator, beam transport system, and beam delivery system, which give priority to these parameters, resulted in the general specifications ultimately agreed upon by PTCOG. These guidelines formed the basis for engineering specifications developed by Fermilab. The accelerator selected was a synchrotron, an elegant

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BT

LOMA LINDA UNIVERSITY MEDICAL CENTER PROTON THERAPY FACILITY LEVEL B Fig. 1. Plan of treatment level (level B), Loma Linda University Medical Center. Beam is generated in the proton accelerator (A, upper right). It is extracted in accordance with each patient’s dose prescription and travels by way of the beam transport system (BT, top) to the appropriate treatment room. The beam is sent to only one room at a time. It is routed to the appropriate room at the main switchyard (MS), which in turn sends it to the fixed-beam room (F) or to either of two gantries (G). Beam directed to the remaining gantry or to the calibration room (C) passes through a second switchyard (S).

system for clinical use as well as for high-energy physics research. Its ability to satisfy the difficult-to-achieve requirements, including rapid, precise energy change and continuous, slow, uniform extraction of the beam, provides the physician with the requisite flexibility for treating patients. The synchrotron’s flexibility enables it to perform well for clinical needs, utilizing either a mechanical scattering system or sophisticated electronic scanning with raster, vozel or other patterns, for precision delivery of the beam to the patient. The transport system was designed with the same flexibility in mind. A system was developed to carry the proton beam through a vacuum tube to the treatment rooms, using large electromagnets to focus and guide the beam to one room at a time. A computerized database provides the information to select the appropriate electric current supplied to each of the magnets, guiding the beam’s direction as it proceeds to the treatment room (Fig. 1). As the beam enters the treatment room it comes under the control of the beam delivery system, which is guided by the patient’s computer-assisted treatment plan. That plan dictates the appropriate energy and number of protons to be delivered to a precise designated volume. The unique requirements for a medical proton accelerator extend to the facility as well. From the outset, it was clear that one could not simply build a proton synchrotron

and drop it in a comer of a building; the building had to be designed in tandem with the accelerator and transport system to optimize the use of both. Accordingly, a structure was designed specifically to house the equipment it would contain and to efficiently manage patient flow. These important aspects, planning the building with its contents and planning the efficient use of both, reduces the otherwise inordinately high cost of utilization of the total system. Close collaboration between the architectural and equipment design teams was imperative because the 5-15’ thick concrete and steel walls could not be adjusted, nor could there be any significant changes in equipment design to accommodate for building errors. Because of the relatively high seismic activity in Southem California, the structure of the building and its contents were all designed to tolerate these events. Design process. Fermilab staff concentrated on the engineering design of the proton synchrotron and its beam transport system, bringing concepts back to PTCOG meetings for discussion over the next 1-2 years after the proposal was accepted by DOE and URA. The gantry design went through many iterations before a modification of a concept proposed by Andreas Koehler of HCL (18) was developed by mechanical engineers from Science Applications International Corporation (SAIC), a large, highly technical firm primarily involved in defense projects. Also

LLU

protontreatmentcenter??JAMES M.

during this period, the NBBJ architectural firm of Seattle was contracted with to develop the building engineering design. This effort required a well-orchestrated series of activities involving the accelerator physics and engineering teams and medical clinical and technical staff, working weekly with the architectural engineers. Clinical personnel at LLU were divided into five groups, each assigned to develop the requirements and conceptual design of a specific area of the facility. Team leaders met at least once a week. Monthly meetings, bringing all team leaders together with the Loma Linda University administration, were held to report, review, and guide progress throughout the entire project. Time-line charts were used to help track the many tasks progressing in parallel to avoid critical path tasks from delaying progress. As the building design reached completion, requests for construction bids were released. McCarthy Western Constructors, Inc. was selected as the general contractor for the project. Construction process. The magnets and most of the components within the accelerator were designed and fabricated at Fermilab. The beam transport system was built in parallel with the accelerator because of time constraints and the similarities in the components of the two systems. Relatively few components were available off the shelf, adding to the cost and time to build the accelerator. It took 1% years to develop the engineering design of the accelerator and transport system and another 2% years to fabricate them. Overall, the design and fabrication process began in mid-1986 and ended in mid-1990. Once completed, the accelerator circulated beam at the first attempt, a very unusual event for such a complex device and representative of the high quality of work done at Fermilab. Groundbreaking for the building occurred in April, 1988. Construction began shortly thereafter and proceeded in parallel with fabrication and testing of the accelerator at Fermilab. Both were ready to come together by September, 1989. Accelerator commissioning was completed at Fermilab in August, 1989. The system then was shut down and disassembled during September and October. The components were labeled and shipped to LLUMC in 12 trucks. Assembly of the accelerator and beam transport systems began in mid-January, 1990; the accelerator became operational in mid-March, 1990. Testing and calibration of the accelerator began immediately and were completed in early April of that year. Extraction studies then began, as the system was analyzed from the accelerator to the eye beam line; these studies were completed by July, 1990, when commissioning began on the first of the treatment beam lines in the fixed-beam room (Fig. 1). In the meantime, the gantries had been delivered from a local fabrication shop and installed. The beam delivery systems for each of the treatment rooms had progressed through the design phase through intense efforts of the LLU and LBL engineering and physics teams. The major portions of the beam delivery hardware and software were developed within the Loma Linda Engineering Laboratory,

SLATERetal.

387

where they were tested and assembled prior to installation within the treatment rooms. Throughout the overall process, many new engineering concepts were developed, resulting in several applications for patents, some of which have been awarded. Over 10,000 new engineering plans have been developed thus far, and more than 300,000 lines of software code have been written. Commissioning and preparation

All components of the system are subjected to a rigorous check-and-recheck process before being used to treat patients. This process has been done on a beam-by-beam basis; that is, as each beam line was being prepared to receive patients, before it was committed to its designed task, it was put through simulated operations. Commissioning of the first beam line, that for patients with tumors of the eye, was completed in October, 1990. Following this, commissioning of the fixed horizontal beam for treating patients with head and neck and brain neoplasms was done, being completed in March, 1991. Assembly of the beam delivery system for the first gantry was completed in April 1991; commissioning was completed in May 1991. Completion of the other two gantry systems and a research room is proceeding. The three gantry treatment rooms will provide for very precise treatment delivery of the proton beam to any anatomic site. Preparation for employing the proton treatment system includes having the requisite personnel to maintain and operate it. These include machine and clinical technicians, electrical engineers, computer scientists, accelerator and clinical physicists, and physicians assigned to the treatment rooms. Dosimetrists familiar with use of three-dimensional treatment planning systems are essential; the plans they develop drive the computer-controlled milling machines for compensator and aperture manufacture, as well as the host computer at each treatment room control station. Clinical technologists must learn many new techniques, such as: operating the computers that control the beam arriving in their treatment room; precise technology for patient positioning; placement of the beam modifiers within the beam delivery system; details and operation of the safety system; and efficiently performing precision patient set-ups. Technologists are critically important in the performance of the proton therapy system: Their interests and talents must be both patient- and technically-oriented. PRESENT STATUS The facility

Construction is substantially complete, though assembly of the hardware on the remaining two gantries and research room remains to be accomplished. This has been deferred pending experience with the first gantry system; improvements or alterations, if required, will be incorporated if such experience dictates. The present focus is on treating

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patients in a systematic manner, using protocols designed to evaluate the applications of proton treatment of various anatomic sites, including intracranial, head and neck, thoracic, abdominal and pelvic regions. The building is constructed primarily on two levels below grade, with a third subterranean level to house the lower portions of the gantry treatment rooms. Each gantry is 3 stories tall and weighs 95 tons. The facility includes physician offices and a single large room with 22 workstation areas for trainees in radiation oncology, engineering, physics, and radiobiology. Patient preparation and set-up areas include mould rooms, CT scanning rooms, simulators, and private dressing rooms. There are five treatment areas in four treatment rooms. An additional beam room is reserved for physics, engineering, and radiobiology studies. Support areas include a suite of rooms and a conference room for treatment planning, physics, and electronics laboratories; a machine shop for fabricating beam-modification devices; patient clinics; and support areas for nurssocial

services,

and similar

ing,

services.

dietetics,

billing,

patient

instruction,

Patients enter through an open-air courtyard from a nearby parking area. An elevator takes patients to the front desk and waiting area, located on the topmost level where the clinics are located. Patients undergoing treatment proceed to the next floor below to the machine areas.

Investigations To optimize the application of proton beams to the clinical situation, several radiobiology and dosimetry studies are being undertaken. The former include in vitro tissue culture studies; microdosimetry studies to measure energy distribution along the beam; and in vivo studies measuring the effects of proton irradiation on the microvasculature and other organs using appropriate animal models. Timedose schedule studies are aimed at reducing overall treatment time, an endpoint made more feasible by the physical dose distribution characteristics of the proton beam. Dosimetry studies are being undertaken to control the amount and dis&ibution of the dose delivered from the advanced-beam delivery system being employed at LLUMC. Commissioning dosimetry is done to characterize and calibrate the beam lines leading to each treatment room. Basic physics studies are underway to provide improved under-

Volume 22, Number 2, 1992

standing of the proton beam’s energy absorption characteristics in tissues. Improved treatment planning dose computation algorithms are being developed to provide more accurate computer simulation of proton treatments. A key aspect of the treatment delivery system is the gradual phasing-in of electronic rather than mechanical beam control. Presently, beam delivery is accomplished in conventional ways: Field size is achieved by means of scattering foils; spreading out the Bragg peak to accommodate tumor thickness is done by a modulator wheel; absorber materials are used in addition to some electronic manipulations to control the depth of the Bragg peak; shaping the beam in the first two dimensions (height and width) is accomplished by cerrobend or brass cut-outs; and beam shaping in the third dimension is achieved by compensators milled on a computer-controlled machine. Hardware and software are being developed and tested to accomplish all of these functions electronically; it is expected that full electronic control will enable us to deliver treatments more efficiently. Operation In October, 1990, the LLUMC Proton Treatment Center began clinical operations, following commissioning of the eye beam line. The first patient was a 35year-old nurse who had been diagnosed with ocular melanoma five weeks before. On October 23rd, she presented for the first of five treatments. Following commissioning of the head and neck beam line, treatments began for patients with brain tumors in March, 1991. By Summer, 1991, patients with tumors in other anatomic sites, initially chest and pelvis, were being treated. Patients are treated according to specific study guidelines, which are now under development at HCL, LBL and LLU. These guidelines, being developed for all anatomic sites, will document the applications of proton treatment in relation to conventional irradiation modalities. This involves a collaborative effort and is being helped by the RTOG neutron study data management group. It is anticipated that the protocols will be made available through RTOG. The proton treatment facility is designed to accommodate a throughput of up to 100 patients per lo-hour day; more may be treated if hours are lengthened. A regional consortium is being developed for referring patients.

REFERENCES 1. Ambrosimov, N. K.; Vorobev, A. A.; Zherbin, E. A.; Konnov, B. A. Proton therapy at the cyclotron at Gatchina, USSR. Proc. Acad. Sci. USSR. X34-91; 1985.

S226; 1985.

2. Archambeau, J. 0.; Bennett, G. W.; Levine, G. S.; Cowen, R.; Akanuma, A. Proton radiation therapy. Radiology 110: 445-457; 1974.

4. Austin-Seymour, M.; Munzenrider, J. E.; Goitein, M.; Verhey, L.; Urie, M.; Gentry, R.; Bimbaum, S.; Ruotolo, D.; McManus, P.; Skates, S. et al. Fractionated proton radiation therapy of chordoma and low-grade chondrosarcoma of the base of the skull. J. Neurosug. 70:13-17; 1989.

3. Austin-Seymour, M.; Munzemider, J. E.; Goitein, M.; Gentry, R.; Gragoudas, E.; Koehler, A. M.; McNulty, P.; Osborne, E.; Ryugo, D. K.; Seddon, J. et al. Progress in lowLET heavy particle therapy: Intracranial and paracranial tumors and uveal melanomas. Radiat. Res. (Suppl) 8:S219-

5. Austin-Seymour, M.; Munzemider, J.; Linggood, R.; Goitein, M.; Verhey, L.; Urie, M.; Gentry, R.; Bimbaum, S.; Routolo, D.; Crowell, C. et al. Fractionated proton radiation therapy of cranial and intracranial tumors. Am. J. Clin. Oncol. 13:327-330; 1990.

LLU proton treatment center 0 JAMESM. SLATERet al.

6. Berry, R. J. Therapeutic uses of x-rays. Int. J. Radiat. Biol. 51(5):873-895; 1987. 7. Blattman, H. (ed.) Proton Therapy of choroidal melanomas (OPTIS). Swiss Institute for Nuclear Research Medical Newsletter. 8:32; 1986. 8. Boone, M. L. M.; Lawrence, J. H.; Connor, W. G.; Morgado, R.; Hicks, J. A.; Brown, R. C. Introduction to the use of protons and heavy ions in radiation therapy: Historical perspective. Int. J. Radiat. Oncol. Biol. Phys. 3:65-69; 1977. 9. Deeley, T. J.; Hale, B. T. The past seventy-five years in radiotherapy. Brit. J. Radiol. 46906-910; 1973. 10. DeVita, V. T. Principles of chemotherapy. In: DeVita, V. T., Hellman, S., Rosenberg, S. A., eds. Cancer: Principles and practice of oncology, 3rd ed. Philadelphia, PA: Lippincott; 1989:276-300. 11. Graffman, S.; Jung, B. Clinical trials in radiotherapy and the merits of high energy protons. Acta. Radiol. Ther. Phys. Biol. 9:1023; 1970. 12. Graffman, S.; Brahme, A.; Larsson, B. Proton radiotherapy with the Uppsala cyclotron: Experience and plans. Strahlentherapie. 161:764-770; 1985. 13. Gragoudas, E. S.; Seddon, J.; Goitein, M.; Verhey, L.; Munzenrider, J. ; Urie, M.; Suit, H. D.; Blitzer, P.; Koehler, A. M. Current results of proton beam irradiation of uveal melanomas. Ophthalmol. 92:294-291; 1985. 14. Gragoudas, E. S.; Seddon, J. M.; Egan, K.; Munzenrider, J.; Austin-Seymour, M.; Goitein, M.; Verhey, L.; Koehler, A. Long-term results of proton beam irradiated uveal melanomas. Ophthalmol. 94:349-353; 1987. 15. Kaplan, H. S. Historic milestones in radiobiology and radiation therapy. Semin. Oncol. 6:479-489; 1979. 16. Kjellberg, R. N.; Shintani, A.; Frantz, A. G.; Kliman, B. Proton-beam therapy in acromegaly . New Eng. J. Med. 309: 689-695; 1968. 17. Kliman, B.; Kjellberg, R. N.; Swisher, B.; Butler, W. Proton beam therapy of acromegaly: A 20-year experience. Prog. Endocr. Res. Ther. 1:191-211; 1984. 18. Koehler, A. M. Preliminary design study for a corkscrew gantry. In: Proceedings of the fifth PTCOG meeting: International workshop on biomedical accelerators. Lawrence Berkeley Laboratory, Dec. l-2, 1986 (Publication #LBL22962). Berkeley, CA: Lawrence Berkeley Laboratory; 1987:147-158. 19. Larsson, B.; Leksell, L.; Rexed, B. The use of high energy protons for cerebral surgery in man. Acta. Chir. Stand. 125: l-7; 1963. 20. Larsson, B.; Liden, K.; Sarby, B. Irradiation of small structures through the intact skull. Acta. Radiol. Ther. Phys. Biol. 13:512-534; 1974. 21. Minakova, E. I.; Kirpatovskaia, L. E.; Liass, F. M.; Snigireva, R. I.; Krymskil, V. A. Proton therapy of pituitary adenomas. Med. Radiol. (Mosk.) 28:7-14; 1983. 22. Munzenrider, J. E.; Gragoudas, E. S.; Seddon, J. M.; Sisterson, J.; McNulty, P.; Bimbaum, S.; Johnson, K.; AustinSeymour, M.; Slater, J.; Goitein, M. M. et al. Conservative treatment of uveal melanomas: Possibility of eye retention after proton treatment. Int. J. Radiat. Oncol. Biol. Phys. 15: 553-558; 1988. 23. Munzenrider, J. E.; Verhey, L. J.; Gragoudas, E. S.; Seddon, J. M.; Urie, M.; Gentry, R.; Bimbaum, S.; Ruotolo, D. M.; Crowell, C.; McManus, P. et al. Conservative treatment of uveal melanoma: Local recurrence after proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 17:493498; 1989. 24. Parker, R. G. Particle radiation therapy: Current status and

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future potential. Cancer. 39:802-805; 1977. 25. Pierquin, B. The destiny of brachytherapy in oncology. Am. J. Roentgenol. 127:495499; 1976. 26. Proton Therapy Co-operative Group (PTCOG). World-wide charged particle patient totals. Particles (Newsletter of the Proton Therapy Co-operative Group). 7:lO; January, 1991. 27. Rosenberg, S. A. Principles of surgical oncology. In: DeVita, V. T.; Hellman, S.; Rosenberg, S. A. eds. Cancer: Principles and practice of oncology 3rd ed. Philadelphia, PA: Lippincott; 1989:23&246. 28. Saunders, W. M.; Char, D. H.; Quivey, J. M.; Castro, J. R.; Chen, G. T. Y.; Collier, J. M.; Cartigny, A.; Blakely, E. A. ; Lyman, J. T.; Zink, S. R.; Tobias, C. A. Precision, high dose radiotherapy: Helium ion treatment of uveal melanoma. Int. J. Radiat. Oncol. Biol. Phys. 11:227-233; 1985. 29. Saunders, W. M.; Chen, G. T. Y.; Austin-Seymour, M.; Castro, 3. R.; Collier, M.; Gauger, G.; Gutin, P.; Phillips, T. L.; Pitluck, S.; Walton, R. E.; Zink, S. R. Precision, high dose radiotherapy: II. Helium ion treatment of tumors adjacent to critical central nervous system structures. Int. J. Radiat. Oncol. Biol. Phys. 11:1339-1347; 1985. 30. Silverberg, E.; Boring, C. C.; Squires, T. S. Cancer statistics, 1990. CA-A cancer journal for clinicians. 40(1):9-27; 1990. 31. Slater, J. M.; Miller, D. W.; Archambeau, J. 0. Development of a hospital-based proton beam treatment center. Int. J. Radiat. Oncol. Biol. Phys. 14:761-775; 1988. 32. Stein, B. M.; Mohr, J. P. Proton therapy for arteriovenous malformations of the brain. New Eng. J. Med. 3 10:656-657; 1984. 33. Suit, H. D.; Goitein, M.; Tepper, J.; Koehler, A. M.; Schmidt, R. A.; Schneider, R. Exploratory study of proton radiation therapy using large field techniques and fractionated dose schedules. Cancer. 35:1646-1657; 1975. 34. Suit, H. D.; Goitein, M.; Munzenrider, J. E.; Verhey, L.; Gragoudas, E.; Koehler, A. M.; Urano, M.; Shipley, W. U.; Linggood, R. M.; Friedberg, C.; Wagner, M. Clinical experience with proton beam radiation therapy. J. Canad. Assoc. Radiol. 31:35-39; 1980. 35. Suit, H. D.; Goitein, M.; Munzenrider, J.; Verhey, L.; Davis, K. R.; Koehler, A. M.; Lingood, R. M.; Ojemann, R. G. Definitive radiation therapy for chordoma and chondrosarcoma of base of skull and cervical spine. J. Neurosurg. 56:377-385; 1982. 36. Suit, H. D.; Miralbell, R. Potential impact of improvements in radiation therapy on quality of life and survival. Int. J. Radiat. Oncol. Biol. Phys. 16:891-895; 1989. 37. Tapley, N. duV. High-energy photon and electron beam. Cancer. 39:788-801; 1977. 38. Tobias, C. A.; Lawrence, J. H.; Lyman, J.; Born, J. L.; Gottschalk, A.; Linfoot, J.; McDonald, J. Progress report on pituitary irradiation. In: Haley, T. J., Snider, R. S., eds. Response of the nervous system to ionizing irradiation. New York, NY: Little, Brown & Co., 1964:19-35. 39. Tobias, C. A.; Roberts, J. E.; Lawrence, J. H.; Low-Beer, B. V. A.; Anger, H. 0.; Born, J. L.; McCombs, R.; Huggins, C. Irradiation hypophysectomy and related studies using 340 MeV protons and 190 MeV duetrons. Peaceful uses of atomic energy. 10:95-96; 1956. 40. Tsunemoto, H.; Morita, S.; Ishikawa, T.; Furukawa, S.; Kawachi, K.; Kanai, T.; Ohara, H.; Kitagawa, T.; Inada, T. Proton therapy in Japan. Radiat. Res. 8(Suppl):S235-S243; 1985. 41. Wilson, R. R. Radiological use of fast protons. Radiology. 47:487491; 1946.