Particle Radiation Therapy: Requiem or Reveille Leslie L. Alexander, MD, FACR, Alfred L. Goldson, MD, and George A. Alexander, MD New York, New York, and Washington, DC
The 1960s and 1970s witnessed a surge of many institutions devoted to electron therapy. Currently, many facilities are adding or have added particle types of radiation to their armamentarium against cancer. The authors review the concepts, problems, and potentials of this form of therapy. The first recorded "dermatitis" of the hand from the radiant energy of a Crookes tube was recorded in 1895, one year before the discovery of x-rays by Roentgen.' Some seven years later an editorial of the Journal of the American Medical Association noted that "the therapeutic effect of x-rays is beginning to be one of the most prominent features in the medical and surgical horizon," and although, "yet in its infancy a wise conservativism is advisable as regards its future."2 Since that time radiation therapy has continued to be an exciting and promising area in medicine. It is estimated that at least 50 percent of patients with cancer receive radiation treatments at some time during their illness. Despite significant advances in radiation treatment using superficial, kilovoltage and megavoltage units, including the skin-sparing cobalt beam with its reduced morbidity, higher dose rates, shorter treatment times, and sharply defined beams, many localized tumors are not eradicated. This inability to control local tumors satisfactorily has prompted the use of betatrons and linear accelerators with electron beams that are variable in
penetration, with deeper tissue sparing and selectivity, and produce even greater effects on relatively resistant tumors. These are the low linearenergy transfer (LET) types of radiation with an energy range of from a few MeV to below 50 MeV.
Particle Radiation Despite this surge to electron therapy in the 1960s and early 1970s, many facilities are adding or have added particle types of radiation to their armamentarium against cancer. Dormant for nearly 40 years, the use of the cyclotron for the treatment of cancer was revived.3 Particle radiation includes:
Protons and Other Heavy Ion Beams Protons and other heavy ion beams have a larger mass, less scatter, precision localization, and sharply defined ranges in tissue. Some examples of these are helium, carbon, neon, nitrogen, and oxygen. They give high value LET spectra of radiation.
Fast Neutrons Presented to the Section on Radiology at the 82nd Convention and Scientific Assembly of the National Medical Association, Los Angeles, August 1-4, 1977. Requests for reprints should be addressed to Dr. Leslie L. Alexander, 1492 President Street, Brooklyn, NY 11213.
Fast neutrons release heavy particles (protons, deuterons, alpha particles, or recoiling nuclei of carbon, oxygen, or nitrogen)4 with greater energy loss (high LET), improved oxygen enhancement ratios (OER), and rela-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
tive biological effect (RBE), and a greater effect on anoxic tumor cells. Fast neutrons do scatter widely, however, and adjacent and, thus, intervening normal tissues are not spared. In addition, their exponential absorption in tissue makes them less desirable.3'5-7 An example of a linear-type accelerator neutron therapy facility is located at the Los Alamos Scientific Laboratory of the University of California (Figure 1). Conceptual drawings of cyclotron injector-synchrotron ring accelerator neutron and heavy ion radiation therapy facilities are shown in Figures 2 and 3. Massive size is an impressive feature. Here energy ranges up to 600-645 MeV and 800 MeV may be generated for scientific research, patient treatment, and the production of radionuclides and radiopharmaceuticals.t0
Pions Negative pi mesons (pions) are charged particles weighing up to 273 times as much as an electron. Because they are charged they may be captured, focused by means of magnetic fields as 800 MeV high LET particles with an insignificant tissue-entry dose, and a depth dose or predetermined stopping range commensurate with the kinetic energy. There is an exquisite sparing of adjacent normal tissues, and an appreciable RBE.10"1l Because of the anticipated increased benefits to patients with cancer who have failed under conventional treatment modalities and to those with relatively resistant cancers, a great deal of research has been conducted with fast neutrons and with pions. So intense has been the interest that a series of international conferences have been held to bring researchers together to discuss the problems and portents of particle 149
radiation therapy. This research has been sponsored by the National Science Foundation and the National Cancer Institute in association with the American College of Radiology, the American Society of Therapeutic Radiologists, and the American Radium Society. Many American, Japanese, and British universities and hospitals are participating, and in the United States there are several regional neutron therapy centers with facilities available for medical treatment. That clinical trials have been effective in large measure was grossly apparent at the particle conference held in 1976 at the Lawrence Berkeley Laboratory of the University of California.8 The number of active programs, however, is small and further full clinical trials are in progress. Some 43 states reported 833 particle accelerators in 516 facilities in the United States. These are presumed to be used primarily for research purposes and for the production of radionuclides. 12 Although commercial cyclotrons are available here in the United States (Clyclotron) and in Europe (Haefely) many limitations on these types of treatment have been noted. The American Society of Therapeutic Radiologists and the American College of Radiology long have recognized the great need for further research with heavy particles (Brady LW, personal communication, April 10, 1978).13.1 Inasmuch as some of the problems remain unanswered, namely, RBE, effect of high LET radiation on various human organ systems, the effect of hypoxic cells, choice of most suitable and effective energy levels, comparative effects of available variable energies, inability to define the precise extent of the tumor, sparing of normal tissues, adequate and precise beam collimation, the physical distribution of the beam,'5
patient-positioning imperfections, computerized treatment planning dosimetry and beam-optics control, including reliability considerations, erstwhile anecdotal observations no longer can be tolerated.
Logistical and Financial Problems When compared to the logistical and 150
PROTON LINEAR ACCELERATOR NEUTRON THERAPY FACILITY Figure 1. Neutron beams are produced by 35MeV protons propelled by the LASL linear accelerator (behind cutout in wall) upon interception by a beryllium target within the rotatable treatment gantry. (Courtesy of Dr. Edward A. Knapp of the Los Alamos Scientific Laboratory of the University of California).
financial problems, all of the clinical hurdles appear miniscule. Some projected linear accelerators for pion clinical facilities have been noted to be one-half mile long. Figures 2 and 3 depict the enormous amount of space required to house a fast-neutron facility. In addition, vast amounts of sophisticated equipment and engineering and other highly technically skilled personnel are required to operate, maintain, and support these facilities. In terms of patient accessibility and facility availability such centers are remotely isolated and present severe logistical problems. Down time and time required for research purposes also seriously limit that amount of time permitted for patient care. When the long distances travelled by patients (and their assistants or family) and the time required to transport these patients are considered, the logistical disadvantages become even more weighty. It has been estimated that the meson physics facility equipment within the federal government's Los Alamos Scientific Laboratory cost some $100 million.10 Knapp estimates that pion clinical facilities would have a total cost, not including contingencies and escalation, of from 5.5 to 8.9 million 1975 dol-
lars.'"I On the basis of cost and performance analysis, Grunder and Leemann judge the synchrotron to be the most economical source for the heavier ions while conventional cyclotrons seem optimal for an exclusive proton facility.8 There is no doubt that the $100 million cost of the Los Alamos Laboratory represents the pooled resources of many government, state, and university agencies. Much larger expenditures have been devoted to research, such as placing a man on the moon. The transition from research to patient care in recent years, however, has been extremely difficult. Reticence on the part of health planners to permit new hospital construction and allow new hospital beds, and recent federal guidelines to local Health Systems Agencies (HSA), tend to limit high-cost specialty services.'7 Certificates of need are delayed or vetoed outright. Despite the fact that computed tomography (C-T) represents a major milestone in radiologic capability with stupendous patient benefits derived therefrom, C-T approvals have become a political football. Although the Institute of Medicine of the National Academy of Sciences has recommended'8 impartial evaluation and
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
HORIZONTAL SEAM DELIVERY VERTICAL EAM)|N
CaveNROTRON
ROOM
A~~~~~~~~~~~~~~~~~~~~~~~~~ MoedariBS
The 1960s and 1970s witnessed a surge of many institutions devoted to electron therapy. Currently, many facilities are adding or have added particle types of radiation to their armamentarium against cancer. The authors review the concepts, problems, and potentials of this form of therapy. The first recorded "dermatitis" of the hand from the radiant energy of a Crookes tube was recorded in 1895, one year before the discovery of x-rays by Roentgen.' Some seven years later an editorial of the Journal of the American Medical Association noted that "the therapeutic effect of x-rays is beginning to be one of the most prominent features in the medical and surgical horizon," and although, "yet in its infancy a wise conservativism is advisable as regards its future."2 Since that time radiation therapy has continued to be an exciting and promising area in medicine. It is estimated that at least 50 percent of patients with cancer receive radiation treatments at some time during their illness. Despite significant advances in radiation treatment using superficial, kilovoltage and megavoltage units, including the skin-sparing cobalt beam with its reduced morbidity, higher dose rates, shorter treatment times, and sharply defined beams, many localized tumors are not eradicated. This inability to control local tumors satisfactorily has prompted the use of betatrons and linear accelerators with electron beams that are variable in
penetration, with deeper tissue sparing and selectivity, and produce even greater effects on relatively resistant tumors. These are the low linearenergy transfer (LET) types of radiation with an energy range of from a few MeV to below 50 MeV.
Particle Radiation Despite this surge to electron therapy in the 1960s and early 1970s, many facilities are adding or have added particle types of radiation to their armamentarium against cancer. Dormant for nearly 40 years, the use of the cyclotron for the treatment of cancer was revived.3 Particle radiation includes:
Protons and Other Heavy Ion Beams Protons and other heavy ion beams have a larger mass, less scatter, precision localization, and sharply defined ranges in tissue. Some examples of these are helium, carbon, neon, nitrogen, and oxygen. They give high value LET spectra of radiation.
Fast Neutrons Presented to the Section on Radiology at the 82nd Convention and Scientific Assembly of the National Medical Association, Los Angeles, August 1-4, 1977. Requests for reprints should be addressed to Dr. Leslie L. Alexander, 1492 President Street, Brooklyn, NY 11213.
Fast neutrons release heavy particles (protons, deuterons, alpha particles, or recoiling nuclei of carbon, oxygen, or nitrogen)4 with greater energy loss (high LET), improved oxygen enhancement ratios (OER), and rela-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
tive biological effect (RBE), and a greater effect on anoxic tumor cells. Fast neutrons do scatter widely, however, and adjacent and, thus, intervening normal tissues are not spared. In addition, their exponential absorption in tissue makes them less desirable.3'5-7 An example of a linear-type accelerator neutron therapy facility is located at the Los Alamos Scientific Laboratory of the University of California (Figure 1). Conceptual drawings of cyclotron injector-synchrotron ring accelerator neutron and heavy ion radiation therapy facilities are shown in Figures 2 and 3. Massive size is an impressive feature. Here energy ranges up to 600-645 MeV and 800 MeV may be generated for scientific research, patient treatment, and the production of radionuclides and radiopharmaceuticals.t0
Pions Negative pi mesons (pions) are charged particles weighing up to 273 times as much as an electron. Because they are charged they may be captured, focused by means of magnetic fields as 800 MeV high LET particles with an insignificant tissue-entry dose, and a depth dose or predetermined stopping range commensurate with the kinetic energy. There is an exquisite sparing of adjacent normal tissues, and an appreciable RBE.10"1l Because of the anticipated increased benefits to patients with cancer who have failed under conventional treatment modalities and to those with relatively resistant cancers, a great deal of research has been conducted with fast neutrons and with pions. So intense has been the interest that a series of international conferences have been held to bring researchers together to discuss the problems and portents of particle 149
radiation therapy. This research has been sponsored by the National Science Foundation and the National Cancer Institute in association with the American College of Radiology, the American Society of Therapeutic Radiologists, and the American Radium Society. Many American, Japanese, and British universities and hospitals are participating, and in the United States there are several regional neutron therapy centers with facilities available for medical treatment. That clinical trials have been effective in large measure was grossly apparent at the particle conference held in 1976 at the Lawrence Berkeley Laboratory of the University of California.8 The number of active programs, however, is small and further full clinical trials are in progress. Some 43 states reported 833 particle accelerators in 516 facilities in the United States. These are presumed to be used primarily for research purposes and for the production of radionuclides. 12 Although commercial cyclotrons are available here in the United States (Clyclotron) and in Europe (Haefely) many limitations on these types of treatment have been noted. The American Society of Therapeutic Radiologists and the American College of Radiology long have recognized the great need for further research with heavy particles (Brady LW, personal communication, April 10, 1978).13.1 Inasmuch as some of the problems remain unanswered, namely, RBE, effect of high LET radiation on various human organ systems, the effect of hypoxic cells, choice of most suitable and effective energy levels, comparative effects of available variable energies, inability to define the precise extent of the tumor, sparing of normal tissues, adequate and precise beam collimation, the physical distribution of the beam,'5
patient-positioning imperfections, computerized treatment planning dosimetry and beam-optics control, including reliability considerations, erstwhile anecdotal observations no longer can be tolerated.
Logistical and Financial Problems When compared to the logistical and 150
PROTON LINEAR ACCELERATOR NEUTRON THERAPY FACILITY Figure 1. Neutron beams are produced by 35MeV protons propelled by the LASL linear accelerator (behind cutout in wall) upon interception by a beryllium target within the rotatable treatment gantry. (Courtesy of Dr. Edward A. Knapp of the Los Alamos Scientific Laboratory of the University of California).
financial problems, all of the clinical hurdles appear miniscule. Some projected linear accelerators for pion clinical facilities have been noted to be one-half mile long. Figures 2 and 3 depict the enormous amount of space required to house a fast-neutron facility. In addition, vast amounts of sophisticated equipment and engineering and other highly technically skilled personnel are required to operate, maintain, and support these facilities. In terms of patient accessibility and facility availability such centers are remotely isolated and present severe logistical problems. Down time and time required for research purposes also seriously limit that amount of time permitted for patient care. When the long distances travelled by patients (and their assistants or family) and the time required to transport these patients are considered, the logistical disadvantages become even more weighty. It has been estimated that the meson physics facility equipment within the federal government's Los Alamos Scientific Laboratory cost some $100 million.10 Knapp estimates that pion clinical facilities would have a total cost, not including contingencies and escalation, of from 5.5 to 8.9 million 1975 dol-
lars.'"I On the basis of cost and performance analysis, Grunder and Leemann judge the synchrotron to be the most economical source for the heavier ions while conventional cyclotrons seem optimal for an exclusive proton facility.8 There is no doubt that the $100 million cost of the Los Alamos Laboratory represents the pooled resources of many government, state, and university agencies. Much larger expenditures have been devoted to research, such as placing a man on the moon. The transition from research to patient care in recent years, however, has been extremely difficult. Reticence on the part of health planners to permit new hospital construction and allow new hospital beds, and recent federal guidelines to local Health Systems Agencies (HSA), tend to limit high-cost specialty services.'7 Certificates of need are delayed or vetoed outright. Despite the fact that computed tomography (C-T) represents a major milestone in radiologic capability with stupendous patient benefits derived therefrom, C-T approvals have become a political football. Although the Institute of Medicine of the National Academy of Sciences has recommended'8 impartial evaluation and
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 2, 1979
HORIZONTAL SEAM DELIVERY VERTICAL EAM)|N
CaveNROTRON
ROOM
A~~~~~~~~~~~~~~~~~~~~~~~~~ MoedariBS
