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Reflections |
1 From the Department of Radiation Oncology, MCP-Hahnemann University, Broad and Vine Sts, MS 200, Philadelphia, PA 19102 (L.W.B.); Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pa (S.K.); Department of Therapeutic Radiology, University of Minnesota, Minneapolis (S.H.L.); Department of Radiation Oncology, University of California at Los Angeles (R.G.P.); and the Department of Radiation Oncology, Wayne State University, Detroit, Mich (W.E.P.). Received April 11, 2000; revision requested May 26; revision received August 28; accepted August 30. Address correspondence to L.W.B. (e-mail: lwb23@drexel.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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Index terms: Neoplasms, experimental studies • Radiobiology • Radiology and radiologists, history • Radiology and radiologists, research • Reflections • Therapeutic radiology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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The recognition of the value of radiation therapy in the treatment of malignant disease and the beginnings of the field of clinical radiation oncology began at the International Congress of Oncology in Paris in 1922 when Coutard, Regaud, and Hautant presented evidence that advanced laryngeal cancer could be cured without disastrous treatment-produced sequelae. By 1934, Coutard had developed a protracted fractionated scheme that remains the basis for current radiation therapy (5). The use of brachytherapy, starting with radium 226 in tubes, increased steadily after 1910 in the treatment of malignant tumors in many different anatomic sites.
With time, ionizing radiation therapy was defined more precisely, and treatment planning and delivery systems became more accurate and reproducible. X-ray generators operating at 800–1,000 kV were installed for medical use as early as 1932.
Simeon Cantril, MD, Franz Buschke, MD, and Herbert Parker, PhD, introduced "supervoltage roentgenotherapy" to the cancer treatment armamentarium in 1932. At that point, two 800-kV x-ray generators were made by General Electric; one was installed at Mercy Hospital in Chicago, Illinois, and apparently never worked properly. The other went to the Tumor Institute at the Swedish Hospital through the efforts of Nils A. Johanson, MD, who was chief of surgery. The initial work in physics and therapy was not well controlled. In 1938, Cantril and Buschke were hired by Johanson, on the basis of their training at the Curie Institute in Paris and recommendations from Max Cutler, MD, H. Coutard, MD, and Juan del Regato, MD, at the Chicago Tumor Institute. Parker was recruited to join the team because of the quickly recognized physics problems (eg, increased energy, increased penetration, less lateral scattered radiation, skin sparing, decreased absorption in bone).
The 800-kV generator was eventually replaced by a 2-mV Van de Graaff generator. These were rapidly followed by cyclotrons, synchrocyclotrons, betatrons, bevatrons, cobalt 60 teletherapy devices, linear accelerators, and nuclear reactors (6).
Atomic Energy of Canada Limited, or AECL, produced three 60Co sources, shipping one to each of three locations: the Princess Margaret Hospital in Toronto, where Harold Johns, PhD, commissioned the machine for treatment; Saskatchewan, where Thomas A. Watson, MD, was in charge; and the M.D. Anderson Hospital and Tumor Institute, where Gilbert H. Fletcher, MD, and his associate, Leonard Grimmet, PhD, were charged with commissioning the machine. Teletherapy with 60Co was used clinically first by Watson, because Johns and Fletcher and Grimmet spent more time evaluating the dosimetry of the sources. Developments rapidly followed, with the first 60Co rotational unit becoming operational at the University of Michigan in 1954. Radionuclides such as 60Co, cesium 137, iridium 192, palladium 103, ruthenium 109, and iodine 125 supplemented 226Ra brachytherapy techniques (7). There continues to be major growth in the knowledge of radiation therapy physics, radiation biology, clinical treatment planning, and the use of computers in radiation therapy.
The past 50 years, and particularly the past 2 decades, have witnessed considerable advances in the treatment of cancer, with cure now being a realistic therapeutic objective in a majority of patients. Many forms of disseminated cancers can be effectively palliated with prolongation of comfortable life with a substantial degree of quality. Clearly, the basic foundations in clinical radiation oncology were laid by del Regato, Fletcher, Henry Kaplan, MD, and William Moss, MD.
In the year 2000, the American Cancer Society estimated that in the United States 1,220,100 new cases of invasive cancer would be diagnosed (8). About 60% of those patients will present with local and/or regional extension that is identified with the new imaging procedures. About 56%–60% of those will be cured by using standard accepted treatment technologies.
A considerable proportion of patients will die, however, because of failure to control the disease locally and regionally. This is particularly true in patients who have malignant tumors of the head and neck; gastrointestinal tract; gynecologic system; genitourinary system; and skin, bone, and soft tissue (9). To improve the potential for local control, concurrent multiple therapies have been investigated. These include brachytherapy with external-beam radiation therapy and/or surgery, surgery and radiation therapy, intravenous chemotherapy and radiation therapy, intraarterial chemotherapy and radiation therapy, particle radiation, and radiation with hyperthermia (10).
Improvements in therapy can be attributed to progress in several major areas as follows:
1. Improvement in diagnostic and screening tools to promote awareness and earlier detection. This is illustrated dramatically by the shift toward earlier diagnosis in breast cancer predicated on early screening technologies, the use of prostate-specific antigen for prostate cancer diagnosis, the emergence of new gene studies for diagnosis, and anticipated outcome.
2. Interdisciplinary communication among cancer surgeons, radiation oncologists, medical oncologists, gynecologic oncologists, pediatric oncologists, diagnostic radiologists, and pathologists that leads to a combined integrated multimodal approach in the treatment of cancer. This is illustrated clearly by the combination of preoperative radiation therapy with continuous infusion chemotherapy, followed by more conservative surgical resection techniques in carcinomas of the rectum.
3. Closer interaction among physicians in the basic sciences, which allows for the transfer of clinically useful biomedical discoveries to the bedside. The development of appropriate clinical trial methodology has improved considerably in its ability to help distinguish between small differences and no differences in the comparison of two alternative treatment programs, as well as associated morbidity and mortality.
4. The emergence of cancer chemotherapy and the subspecialty of medical oncology with an emphasis on combined modality treatment.
During the Second World War, two 2-million-volt Van de Graaff generators were developed for the diagnostic assessment of steel plates for ships in the navy. These two units were installed after the war, one at the United States Naval Hospital in Bethesda, Maryland, and the other at the American Oncologic Hospital in Philadelphia, with another at the Swedish Hospital in 1950. Much of the early data relative to clinical treatment planning, dosimetry, and clinical applications for accelerators were gained by using these machines (11).
From this, the beginning of high-energy technology for accelerators and 60Co teletherapy units in modern contemporary radiation oncology started. In 1957, the Donner Foundation gave 10 2-million-volt Van de Graaff generators to various institutions in the United States to assess their value in the treatment of cancer. Emerging from this progress, the emphasis on high-energy technology, supported by carefully assessed physics and the implementation of basic biologic principles into cancer management, emerged to be the foundation for contemporary practice in radiation oncology.
In 1955, the Cancer Chemotherapy National Service Center called a meeting of outstanding general radiologists at the Stone House at the National Cancer Institute. The purpose of the meeting was to identify the needs for clinical trials in radiation oncology. From these meetings, the initial recommendations did not help to identify any areas of major clinical investigation in radiation oncology.
In 1960, del Regato, not willing to accept this lack of recommendations, pointed out to the Clinical Studies Panel of the National Cancer Institute that there were at least three major areas for possible cooperation in combined modality treatment that needed further investigation. These were the investigation of chemotherapeutic agents as radiotherapeutic adjuvants, the investigation of agents capable of specifically potentiating the biologic effects of ionizing radiations, and radiation therapy in comparison with chemotherapy as a surgical adjuvant (12). This was at a time when investigations into the applications of chemotherapeutic agents were being pursued as a possible sole answer in the treatment of cancer. Despite discouraging results when these agents were used alone, investigators did indicate that further efforts were justified.
del Regato went on to point out that chemotherapeutic agents had been used in conjunction with radiation therapy in the palliative treatment of several manifestations of cancer, in particular radiation therapy and nitrogen mustard in the management of Hodgkin disease, with major emphasis on radiation therapy (12). The periodic administration of chemotherapeutic agents in the course of long-term radiation therapy was thought to prove fruitful in the treatment of radiocurable, as well as heretofore nonradiocurable, tumors. The amounts, periodicity, and intervals would need to be the subject of continued investigations, in particular in cancers of the cervix, lung, and breast and in chronic leukemias.
There continued to be data presented identifying the enhancement of the selected effects of radiation on tumor cells with other treatment agents, such as diathermy, hormones, oxygen, and menadiol sodium diphosphate (12). The continued discussions indicated that clinical trials with newer-developing chemotherapeutic agents in the 1960s, such as actinomycin D, cyclophosphamide, and 5-fluorouracil, should be explored in combination with radiation therapy. The search for new products having potentiating effects with low toxicity would allow for their repetitive use during courses of radiation therapy.
del Regato continued to point out that there should be major investigations into the optimization of radiation therapy with surgery or chemotherapy, or how all three treatment modalities could be integrated into a multimodal approach to maximize the potentials for control and cure and minimize the potentials for complications (12). It is from this point that the evolution of major interspecialty cooperative efforts sprung. Better integration of treatment was necessary. It was obvious that these potential improved results would be more fruitful and dramatic in character when performed in well-organized randomized clinical trials.
Subsequent to the catalyzing influence of del Regato’s presentations, the Subcommittee on Cancer of the Breast of the Surgical Adjuvant Committee proposed a cooperative experiment in which chemotherapy, postoperative radiation therapy, and castration would be randomized after radical mastectomy (12). Efforts were needed to standardize the quality and character of the radiation therapy approach not only in terms of fields to be used but also in terms of fractionation, protraction, daily doses, and total doses. Even though the expectation was to establish the futility of postoperative radiation therapy in the management of cancer of the breast, only now, as del Regato pointed out, is a definite benefit in selected groups of patients beginning to emerge. The evolution of events in radiation therapy after mastectomy has ranged from all patients receiving postoperative radiation therapy after mastectomy in the 1950s and 1960s, to where few received treatment in the 1970s and 1980s, to where now there is recognized benefit that will accrue in the combination of the treatment regimens (12).
Suggestions were made for assessing the proper integration of surgery and radiation therapy in malignant tumors of the thyroid gland. Suggestions were also made for the appropriate use of radiation therapy with surgery and/or chemotherapy in carcinoma of the lung (12).
In 1960, it was obvious that there were unquestioned difficulties in performing experiments in association with radiation therapy.
1. There was the dispersion of human material, a characteristic trend of American medicine, working to the disadvantage of radiation therapy. It is only now that radiation therapy technologies and skills have allowed for maximization of benefits from radiation therapy, a development seen earlier from skillful surgeons and developing operating room technologies.
2. Some outstanding institutions that could have contributed a large number of patients in clinical trials were unwilling to participate in clinical trials, a situation that has corrected itself considerably in the past 10 years.
3. Practiced techniques of radiation therapy were far more varied, as were surgical techniques. However, in the last years of the 20th century, standardization of radiation therapy technologies was achieved, and there is a more consistently uniform practice in all areas of radiation oncology.
4. Clinical trials in radiation therapy were not as easily judged on a short-term basis because their benefits were not always immediately evident at biometric analysis. There was a need for long-term follow-up with the emphasis on cure rather than the short-term follow-up emphasis on palliation (12).
From the discussions at Stone House in 1955 and at the subsequent presentations to the Clinical Studies Panel of the National Cancer Institute, the Radiation Study Section of the National Cancer Institute was formed. This group was composed of outstanding talent in radiation oncology in the United States and Canada, including clinicians, physicists, and biologists with a charge to develop cooperative studies in radiation biology and radiation physics, as well as their applications in clinical radiation therapy (12). The emphasis on communication of new data resulted in a series of conferences, the first of which was held in Highland Park, Illinois, in 1959, the second in May 1960 in Carmel, California, followed by many others that have had dramatic catalyzing effects on communication of information and data from treatment and presenting foundations for clinical trials (12). Group studies favored collective reporting for comparison of results; and through Committees on Cancer of the Lung, Cancer of the Cervix, and so on, protocols were developed and discussed, and clinical trials were initiated.
It was from these early midcentury beginnings that the radiation oncology community was catalyzed to act. This led to the creation of the Committee for Radiation Therapy Studies (CRTS) at the suggestion of Kenneth Endicott, MD, then director of the National Cancer Institute, to advise the director of the National Cancer Institute on appropriate studies in radiation oncology (12). The first chairman of that committee was Gilbert H. Fletcher, MD. With the cooperation of the outstanding leaders in radiation oncology, this committee galvanized the field of radiation oncology.
The CRTS set the standards for clinical practice ultimately identified and documented by Simon Kramer, MD, through the patterns of care study. The CRTS was responsible for the creation of the Radiation Therapy Oncology Group (RTOG), the first chairman of which was Kramer. The CRTS proposed and developed the "blue books," which set the standards for radiation therapy practice in terms of resources, facilities, and personnel. They were published first in 1972 (13–16) and then revised in 1981, 1986, and 1991. The CRTS developed and published the Radiation Research Plans for Radiation Oncology first in 1976, edited by Kramer, followed by updates in 1979, 1982, and 1987 (edited by Brady et al) (17–20).
The CRTS, subsequently the Committee for Radiation Oncology Studies (CROS), chaired first by Fletcher and followed by Kramer, William E. Powers, MD, and finally Luther W. Brady, MD, assumed a new role as the Inter-Society Council for Radiation Oncology, chaired first by Brady and subsequently by James D. Cox, MD, Gerald E. Hanks, MD, and John D. Earle, MD. The creation of the Inter-Society Council for Radiation Oncology resulted as a joint cooperative effort among national societies in radiation oncology, with funding from those societies dictated by the loss of support from the National Cancer Institute. In the beginning, the major societies in radiation oncology included the American Society for Therapeutic Radiology and Oncology, the American Radium Society, the Radiological Society of North America, the American Association of Physicists in Medicine, the Radiation Research Society, the Society for Chairmen of Radiation Oncology Programs, and the American College of Radiology. Other societies subsequently became a part of this joint effort.
The members of the CRTS and subsequently the CROS illustrate the breadth and depth and the expertise and leadership of the group of radiation oncologists who set the foundations for contemporary radiation oncology in the United States. These are Malcolm A. Bagshaw, MD, Fernando G. Bloedorn, MD (deceased), Max L. M. Boone, MD (deceased), Luther W. Brady, MD (CROS chair), G. Stephen Brown, MD, James D. Cox, MD, Juan A. del Regato, MD (deceased), James R. Eltringham, MD, Gilbert H. Fletcher, MD (CROS chair; deceased), Milton Friedman, MD (deceased), Manuel Garcia, MD (deceased), Eric J. Hall, DSc, Samuel Hellman, MD, Frank R. Hendrickson, MD, David H. Hussey, MD, Henry S. Kaplan, MD (deceased), Morton M. Kligerman, MD, C. Ronald Koons, MD, Simon Kramer, MD (CROS chair), Isadore Lampe, MD (deceased), Howard B. Latourette, MD (deceased), Seymour H. Levitt, MD, Victor A. Marcial, MD, Rodney R. Million, MD, William T. Moss, MD, Walter T. Murphy, MD (deceased), James J. Nickson, MD (deceased), Robert G. Parker, MD, Carlos A. Perez, MD, Theodore L. Phillips, MD, William E. Powers, MD (CROS chair), Robert Robbins, MD, Philip Rubin, MD, J. Robert Stewart, MD, Herman D. Suit, MD, DPhil, Norah D. Tapley, MD (deceased), Jerome M. Vaeth, MD (deceased), Richard J. Walton, MD, Thomas A. Watson, MD (deceased), Gordon F. Whitmore, PhD, MSc, Rodney Withers, MD, DSc, and Peter Wootton, BSc.
The RTOG emerged from the CRTS in 1968, funded by the National Cancer Institute in 1971, and has had and continues to have a major and dramatic effect on coordinating all efforts in radiation therapy physics, radiation biology, and the translation of these basic data into cooperative clinical trials that have had a major and substantial effect on the practice of radiation oncology in the United States. These studies have changed substantially, and in a major fashion, the practice of the specialty. Since 1978, more than 50,000 patients have been entered into RTOG studies in more than 369 protocols, and with continued evolution of new protocols to substantiate new premises in the treatment of cancer by using radiation therapy.
In the early 1960s, the National Cancer Institute actively supported the development of training and education programs for radiation oncology and developed major support for basic scientific efforts in radiation biology and radiation therapy physics. It also supported the development of nationally recognized research centers in radiation oncology, with 26 ultimately being designated during the 1960s and 1970s as centers of excellence in radiation oncology.
Brady identified the magnitude of the RTOG contributions in his Gold Medal Address to the American Society for Therapeutic Radiology and Oncology in 1987 (21). The breadth, depth, and magnitude of these studies have set the standard for contemporary practice. One of the high-priority items for the RTOG was the investigation of high linear energy transfer radiations, with specific emphasis on neutron generators, proton generators, and pi meson generators, with regard to their potential contribution in the treatment of patients with cancer (21). It is clear that the present emphasis on proton-beam generators as primary treatment, or as adjuvant treatment to external-beam radiation therapy, indicates the sophistication of the technology available for clinical investigation.
The effect of the clinical trials on multiple disease sites has been substantial because of the improvement in the potential for local and regional control, specifically in tumors of the head and neck; lymphomas; and tumors of the lung, cervix, and prostate. The RTOG is the largest single resource for patients who have been treated in clinical trials, with records of more than 50,000 patients on file at the Statistical Center for the RTOG for ongoing continued assessment. Not only has this effect on local and regional control been substantial, but it has also affected survival. The RTOG has confirmed the potential for organ preservation by using conservation surgery and radiation therapy and has identified the need for combined integrated multimodal treatments with chemotherapy and more conservative surgery in tumor treatment. Clinical trials have confirmed that conservation surgery and radiation therapy in breast cancer provide results that are equivalent to modified radical mastectomy or radical mastectomy (22). Radiation therapy with 5-fluorouracil has substantially affected cancers of the anus, with excellent results that are equivalent to or better than those obtained by means of surgical management with preservation of bowel continuity (23).
No other specialty in oncology has made as much progress in as short a period of time with as many major accomplishments as has the radiation oncology community. Despite many difficulties, the community has functioned in a positive, coherent, cooperative way to maximize the potentials for radiation therapy and to minimize the potentials for complication.
There has been a major shift toward earlier diagnosis at presentation, in particular in cancers of the cervix; there has not only been a reduction in the number of new cases with invasive cancer, which is directly related to more widespread implementation of screening technologies, but there has also been a shift from more advanced disease to earlier stage disease at presentation (24). The same has been true in cancers of the prostate gland and cancers of the breast; most patients now present with early-stage disease (24).
In looking to the future, there are a number of areas that are in development and implementation that have potential for substantial effect on local and regional control, either alone or in combination with chemotherapy. These include not only technical developments relative to three-dimensional reconstructed treatment planning and delivery but also to intensity-modified radiation therapy technologies, the continued acquisition of data from altered fractionation schemes, the better use of integrated brachytherapy technologies, endoscopic radiation therapy, and intraoperative radiation therapy, with the application of more sophisticated statistical techniques and more emphasis on organ preservation (21).
The excitement in contemporary radiation therapy practice has emerged from the basic foundations laid by the CRTS, later the CROS, and later the Inter-Society Council for Radiation Oncology, the effect of the High Linear Energy Transfer Radiation Therapy Program, and RTOG development.
Other events that transpired during that same period included the formation of the American Club for Therapeutic Radiology and Oncology, to become in 1969 the American Society for Therapeutic Radiology and Oncology. The meetings of this organization have grown to be the central focus for presentation of worldwide expert research in radiation oncology. The society has grown to include more than 5,000 members and represents all specialties in radiation oncology.
The development of the International Journal for Radiation Oncology, Biology, and Physics, edited first by Philip Rubin and now by James Cox, is recognized as the premiere publication in radiation oncology. Its subspecialties are managed by the American Society for Therapeutic Radiology and Oncology.
The major textbooks now used in all specialties in radiation oncology have had a substantial effect on illuminating the breadth and depth of radiation oncology. These textbooks include those by Fletcher (25), Moss and Cox (26), Perez and Brady (27), and Leibel and Phillips (28).
The American Board of Radiology has administered examinations in therapeutic radiology since its founding in 1934 as a joint board sponsored by various national radiology organizations. In 1974, the American Society for Therapeutic Radiology and Oncology became a cosponsor of the American Board of Radiology, which has evolved into a more regularized structured system for examination for certification in radiation oncology as a separate specialty under the aegis of the American Board of Radiology. This certification process includes a written examination, with an oral examination after successful completion of the written examination. The interjection of computerized technology into the written and oral examinations makes the examination process for certification more reliable and dependable. The recertification process has now become established.
The radiation oncology community has had a substantial representation in the American College of Radiology since the early 1960s. The American Society for Therapeutic Radiology and Oncology and the American Radium Society are cosponsors of the American College of Radiology, with representation in the council, the steering committee of the council, and the board of chancellors of the organization.
With the evolution of more complex problems relative to reimbursement issues, the American College of Radiation Oncology was founded in New Orleans in 1988 to pursue more actively the interests of radiation oncologists on the national scene for socioeconomic efforts.
As with all living organisms, no situation is ever stable. However, radiation oncology stands on the threshold of incredible promise and fulfillment. It has been made possible by the dedication, leadership, and wisdom that has been brought to the entire field of radiation oncology by dedicated clinicians, by clever and careful biologic research investigators, and by the major contributions made by radiation therapy physicists. As we enter the 3rd millennium, there is even greater potential for controlling cancer with radiation therapy techniques, with a concomitant reduction in complications from these techniques. It is clear that the breadth and depth of participation by the radiation oncology community in all aspects of cancer management continue to be pursued and explored for the potential effect on cancer cure.
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TOPABSTRACTINTRODUCTIONREFERENCES |
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