Journal of the Korean Physical Society, Vol. 50, No. 5, May 2007, pp. 1385∼1389 Review Articles Accelerators and Medicine William T. Chu∗ EO Lawrence Berkeley National Laboratory, Berkeley, California, U.S.A. (Received 22 November 2006) In 1930 Ernest Orlando Lawrence at the University of California, Berkeley invented the cy- clotron, which accelerated protons to 80 keV using less than 1 kV on a semi-circular “dee.” The 60-Inch (150-cm) Cyclotron (1939) that accelerated deuterons to 19 MeV, enabled the first ther- apeutic applications anywhere of artificially produced radioisotopes on human patients, thereby a new medical modality called nuclear medicine was born. Around the world, there are about 100 isotope-producing cyclotrons (accelerating protons, and much less frequently deuterons, to energies in the range of 15-20 MeV). After WWII, Lawrence completed the 184-Inch (4.7-m) Synchrocy- clotron that produced 340-MeV protons. The synchrocyclotrons in Berkeley and Uppsala, together with the Harvard cyclotron, would perform pioneering work in treatment of human cancer using accelerated hadrons. At the 184-Inch, in 1954 Cornelius Tobias and John Lawrence performed the first therapeutic exposure of human patients to hadron (deuteron and helium ion) beams. Clinical trials to treat human cancer using helium ions took place at the 184-Inch and the Bevalac, where trials using heavier ions including carbon, neon, silicon and argon ions were carried out to exploit their biological advantages over proton beams. Aside from the Berkeley trials, other clinical trials have been conducted at more than a dozen physics accelerators around the world. There are now proton and carbon-ion accelerator facilities dedicated for medical use around the world. PACS numbers: 29.20.Hm, 29.20.Lq, 87.52.Df, 87.52.Ln, 87.53.-j Keywords: Accelerator, Cyclotron, Synchrotron, Cancer treatment, Nuclear medicine I. INVENTION OF CYCLOTRON ated deuterons to 19 MeV. It was housed in the Crocker Laboratory, where scientists first made transmutations of some elements, discovered several transuranic ele- The invention of the cyclotron by Ernest Orlando ments, and created hundreds of radioisotopes of known Lawrence at the University of California, Berkeley elements. At the Crocker Laboratory the new medical seventy-five years ago profoundly changed the way we treat human diseases. Lawrence conceived the idea of the cyclotron early in 1929 after reading an article by Rolf Wider¨oeon high-energy accelerators [1]. In the spring of 1930 one of his students, Nels Edlefsen, constructed two crude models of a cyclotron [2]. Later in the fall of the same year, another student, M. Stanley Livingston, constructed a 13-cm diameter model (Fig. 1) that had all the features of early cyclotrons, accelerating protons to 80 keV using less than 1 kV on a semi-circular accel- erating electrode, now called the “dee” [3]. Following the discovery by J. D. Cockcroft and E. T. S. Walton of how to produce larger currents at higher voltages [4], Lawrence constructed the first two- dee 27-Inch (69-cm) Cyclotron, which produced protons and deuterons of 4.8 MeV. The 27-Inch Cyclotron was used extensively in early investigations of nuclear re- actions involving neutrons and artificial radioactivity. In 1939, working with William Brobeck, Lawrence con- structed the 60-Inch (150-cm) Cyclotron, which acceler- Fig. 1. The first cyclotron made by Lawrence and Liv- ingston (1930). ∗E-mail: [email protected] -1385- -1386- Journal of the Korean Physical Society, Vol. 50, No. 5, May 2007 modality called nuclear medicine was born, which used 60-Inch Cyclotron. Their research discovered the nature radioisotopes for diagnosis and treatment of human dis- of decompression sickness, known as the “the bends,” eases. In 1939 Lawrence was awarded the Nobel Prize that many military aviators suffered when flying at high in Physics, and later Element 103 was named “Lawren- altitudes without pressurized suits [5]. It is interesting to cium” in his honor. note that after more than a half century later, 81mKr gas Just before WWII, Lawrence and Brobeck designed is still used at hospitals to yield functional images of pul- the 184-inch cyclotron, but the war prevented the monary ventilation. Now it became routine for nuclear building of this machine. Immediately after the war medicine procedures that use radioisotopes to provide ended, the Veksler-McMillan principle of phase stability diagnostic information about the functioning of a per- was put forward, which enabled the transformation of son’s specific organs, or to treat diseases. The thyroid, conventional cyclotrons to successful synchrocyclotrons. bones, heart, liver and many other organs can be readily When completed, the 184-Inch Synchrocyclotron pro- imaged, and disorders in their function revealed. It is duced 340-MeV protons. Soon after, more modern syn- estimated that 15 to 20 million nuclear medicine imag- chrocyclotrons were built around the globe, notably at ing and therapeutic procedures are performed every year Columbia University, Carnegie Institute of Technology, around the world, and demand for radioisotopes is in- and University of Chicago in the United States, and an- creasing rapidly. In developed countries (about a quarter other in Uppsala, Sweden. The synchrocyclotrons in of world population) the frequency of diagnostic nuclear Berkeley and Uppsala, together with the Harvard cy- medicine procedures performed is approximately two per clotron, would perform pioneering work in treatment of 100 persons per year, and the frequency of therapy with human cancer using accelerated hadrons. radioisotopes is about one tenth of this. In the 1950s larger synchrotrons were built in the GeV A radioisotope used in Single Photon Emission Com- region at Brookhaven (3-GeV Cosmotron) and at Berke- puted Tomography (SPECT) must emit gamma rays of ley (6-GeV Bevatron), which produced antiprotons and sufficient energy to escape from the body yet it must antineutrons, many of the transuranic nuclei, and many have a halflife short enough for most of it to decay away excited states of hadrons. Today most of the world’s soon after imaging is completed. A positron emitter largest accelerators are synchrotrons, such as the 1-TeV with a similarly short halflife is needed in Positron Emis- Tevatron at Fermilab near Chicago and the 450-GeV Su- sion Tomography (PET). PET’s most important clinical per Proton Synchrotron (SPS) at CERN in Switzerland, role is in oncology, where fluorodeoxy glucose (FDG) is and all are direct descendents of Lawrence’s cyclotron used (incorporating 18F as the tracer), due to its accu- invented 75 years ago. racy in detecting and evaluating most cancers in a non- invasive way. It is also used in cardiac and brain imag- ing. Positioning of the radiation source within the body is the fundamental difference between nuclear medicine II. BEGINNING OF NUCLEAR MEDICINE imaging and other imaging techniques such as X-rays. Gamma imaging by either SPECT or PET provides a Lawrence’s interest in building accelerators centered, view of the position and concentration of the radioiso- of course, on nuclear physics; but from the onset he was tope within the body. Organ malfunction can be indi- keenly aware of their important applications in medicine. cated if the isotope is either partially taken up in the To study radiation in medicine, Lawrence brought to organ (a cold spot), or taken up in excess (a hot spot). Berkeley his physician brother, John Hundale Lawrence, If a series of images is taken over a period of time, an M.D., from Yale School of Medicine, who soon demon- unusual pattern or rate of isotope movement could indi- strated the isotope-making cyclotron’s worth in disease cate malfunction in the organ. Nuclear fission reactors research. John Lawrence became Director of the Divi- produce the bulk of medical radioisotopes [6], but iso- sion of Medical Physics at the University of California, topes of very short halflives, especially those for PET, Berkeley. Starting in 1936, John Lawrence operated a are produced by cyclotrons located near PET machines clinic to treat leukemia and polycythemia patients with in hospitals. Around the world, there are about 100 radioactive phosphorus produced at Crocker Laboratory, isotope-producing cyclotrons (accelerating protons, and then the site of the 60-Inch Cyclotron. These were much less frequently deuterons, to energies in the range the first therapeutic applications anywhere of artificially of 15 – 20 MeV). The typical beam power of such a cy- produced radioisotopes on human patients. Thus John clotron is of the order of 15 kW. In the foreseeable future, Lawrence became the “Father of Nuclear Medicine.” >100-MeV cyclotrons, and linacs, with beam power ten Ernest Lawrence himself became a consultant to the In- times greater, will be required to produce isotopes for stitute of Cancer Research at Columbia University. newer nuclear medicine procedures. One of the earliest biomedical uses of radioactive el- Radioisotopes produced at cyclotron facilities for var- ements was research conducted during WWII by John ied nuclear medicine applications include: Positron emit- Lawrence and Cornelius Tobias, another student of ters 11C, 13N, 15O, and 18F, which are used in PET to Ernest Lawrence. They used radioactive nitrogen, argon, study brain physiology and pathology, in particular to krypton, and xenon gases, which were produced at the localize epileptic focus, and in dementia, psychiatry and Accelerators and Medicine – William T. Chu -1387- neuropharmacology