Gold medal address: The radiation therapy oncology group—1987

0360-3016/88 $3.00 + .OO Copyright 0 1988 Pergamon Press plc

Inl. J. Radiarion Oncology Biol. Phys., Vol. 15, pp. 537-542 Printed in the U.S.A. All rights reserved.

0 Special Feature GOLD MEDAL ADDRESS: THE RADIATION THERAPY ONCOLOGY GROUP-1987 LUTHER

W. BRADY,

M.D.

Hylda Cohn/American Cancer Society Professor of Clinical Oncology and Chairman, Department of Radiation Oncology and Nuclear Medicine, Hahnemann University, Philadelphia, PA

therapy techniques. There has been much growth in the knowledge of radiation therapy physics, radiation biology, clinical treatment planning, and the use of computers in radiation therapy. The last 2 decades have witnessed considerable advances in the treatment of cancer, with cure now being a realistic therapeutic objective. Many forms of disseminated tumors can be effectively palliated with prolongation of life. The American Cancer Society estimates that 965,000 new cases of invasive cancer will be diagnosed in 1987.’ Of that number, 7 1% of the patients will present with local and/or regional extension. About 56% of those will be cured by standard treatment techniques. A considerable proportion of patients who die will do so because of failure to control the disease process locally and regionally. This is clearly evident in patients who have malignant tumors of the head and neck, gastrointestinal tract, gynecologic system, genitourinary system, and skin, bone and soft tissue. To improve the potential for local control, multiple therapies have been investigated. These include brachytherapy with radiation and/or surgery, surgery and radiation therapy, intra-arterial chemotherapy and radiation therapy, particle radiations, and hyperthermia. Improvements in therapy can be attributed to progress in several major areas:

RTOG, Clinical radiation oncology.

Roentgen described X rays in 189517 and the Curies7 reported their discovery of radium in 1896. Almost immediately, the biologic effects of ionizing radiations were recognized. In January 1896, the first patient was treated by X rays for a carcinoma of the breast.8 The first patient cured by radiation therapy was reported in 1899 after which clinical radiation therapy had a long and painful growth period to the early 1920s. Many significant and important advances were made during this time, but techniques were inconsistent and often not reproducible. Technologic advances accumulated more rapidly than did basic biologic knowledge. The x-ray tube with a peak energy of 140 KV was developed by Coolidge in 19 13 and by 1922,100 KV X rays were available for deep radiation therapy. The field of clinical radiation oncology began at the International Congress of Oncology in Paris in 1922 when Coutard and Hautant presented evidence that advanced laryngeal cancer could be cured without disastrous treatment produced sequelae. By 1934, Coutard5 had developed a protracted fractionated scheme that remains the basis for current radiation therapy. The use of brachytherapy, starting with radium-226 in tubes, has increased steadily since 19 10 in the treatment of malignant tumors in many anatomic locations. With time, ionizing radiation was defined more precisely and treatment planning and delivery systems became more accurate and reproducible. X-ray generators operating at 800- 1,000 kilovolts were installed for medical use as early as 1932. These were followed by cyclotrons, synchrocyclotrons, betatrons, bevatrons, 6oCo teletherapy devices, linear accelerators, and nuclear reactors. Radioisotopes such as 6oCo, cesium- 137, iridium192, and iodine- 125 supplemented radium-226 brachy-

Improvement in diagnostic and screening tools to promote awareness and early detection. Interdisciplinary communication among cancer surgeons, radiation oncologists, medical oncologists, and pathologists-the combined modality approach in the treatment of cancer. Closer interaction among physicians in basic sciences allowing the transfer of clinically useful biomedical

Accepted for publication

Presented as The Gold Medal Lectureship, American Society for Therapeutic Radiology and Oncology, 20 October 1987, Boston, MA. 537

1 April 1988.

538

I. J. Radiation Oncology 0 Biology 0 Physics

discoveries to the bedside (appropriate clinical trial methodology is still necessary to distinguish between small differences and no differences when comparing two alternative treatment programs), and 4. The emergence of cancer chemotherapy and the subspecialty of medical oncology. However, the growth and development of radiation oncology has not always been smooth and steady. The 1 million volt x-ray generator was installed at the University of California in San Francisco in 1937. Stone” concluded from its use that there was no particular advantage as far as skin sparing was concerned but there was an increase in depth dose. The reason for this was probably related to the cones that were used for treatment.” During the Second World War, two 2 million volt Van de Graaf generators were developed for the diagnostic assessment of steel plates for the Navy. These two units were subsequently installed after the war, one at the United States Naval Hospital in Bethesda, Maryland, and the other at the American Oncologic Hospital in Philadelphia. Much of the early data relative to clinical treatment planning bases of dosimetry and clinical applications of accelerators was gained on these machines. In the late 1940s and early 1950s Kerman working at the Medical Division of the Oak Ridge Institute of Nuclear Studies developed along with Fletcher the first 6oCo units one of which was installed at the M. D. Anderson Hospital in Houston and the other at the Lankenau Hospital in Philadelphia. This was the beginning of high energy technology for accelerators and 6oCo units in modern contemporary radiation oncology. In 1957, the Donner Foundation gave ten 2 million volt Van de Graaf generators to various institutions in the United States to assess their value in the treatment of cancer. It is from these beginnings that the emphasis on high technology supported by carefully assessed physics and the implementation of basic biologic principles into cancer management emerged into the contemporary practice of radiation oncology. In 1955, the Cancer Chemotherapy National Service Center called a meeting of outstanding radiologists at Stone House at the National Cancer Institute. The point of the meeting was to identify the needs for clinical trials in radiation oncology. The initial recommendations did not identify any areas for major clinical investigation in radiation oncology. In 1960, de1 Regato” 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 therapy needing further investigation. These were: (a) the investigation of chemotherapeutic agents as radiotherapeutic adjuvants, (b) the investigation of agents capable of specifically potentiating the biologic effects of radiation, and (c) radiotherapy in comparison with chemotherapy as a surgical adjuvant. This was at a time when investigations into the applications

September 1988, Volume 15, Number 3

of chemotherapeutic agents were being pursued as the possible and sole final answer in the treatment of cancer. Despite discouraging results when these agents were used alone, investigations did indicate further efforts to be justifiable. 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 particularly radiation therapy and nitrogen mustard in the long-range management of Hodgkin’s disease with the major emphasis on radiation therapy. It was pointed out that periodic administration of chemotherapeutic agents in the course of long-term radiotherapy might prove fruitful in the treatment of radiocurable as well as heretofore non-radiocurable tumors. The amounts, the periodicity, the intervals, etc., would need to be the subject of continued investigation. The suggestion was made that possible subjects of research in this area would be the advanced manifestations of cancers of the cervix, lung, breast, chronic leukemias, etc. At that point, the data were presented on efforts to enhance the selective effects of radiation on tumor cells. Even a slight improvement of this selective effect would prove sufficient to turn the circumstances in favor of radiocurability of many tumors. Simultaneous irradiation with diathermy, hormones, oxygen, synkovite, as well as several other agents had been tried sporadically without great evidences of success. The motivating effort was to improve what frequently proved to be insufficient skill in the administration of radiotherapy. At that point, de1 Regato pointed out the need for clinical trials using agents such as Actinomycin-D, Cytoxan, and 5Fluorouracil in combination with radiotherapy. The comment was made that chemists should orient themselves toward the search for new products which might have potentiating effects and low toxicity permitting their repetitive use during the course of radiotherapy. Other possibilities such as the use of oxygen and ultrasound needed to be explored even though their practicality at that time was questionable. The last major area that de1 Regato suggested for major investigation was the use of radiotherapy combined with surgery or chemotherapy with surgery or all three modalities in a multimodal approach to the problem of cancer management. Evidences of the usefuless of these associations was often assumed but actually lacking. Even though the exploitation of better integration of surgery and radiotherapy lacked the glamour of new areas of investigation, even then the potential results appeared to be more fruitful when well organized randomized experiments were carried out with or without chemotherapy. Subsequent to that presentation, the Subcommittee on Cancer of the Breast of the Surgical Adjuvant Committee proposed a cooperative experiment in which chemotherapy, postoperative radiotherapy and castration would be randomized following radical mastectomy.

Gold Medal Address 0 L. W. BRADY

Efforts needed to be directed toward standardization of the radiotherapy approach not only in terms of fields to be employed but dosages to be employed, fractionation, protraction, etc. Even though the expectation was to establish the usefulness or futility of postoperative radiotherapy in the management of cancer of the breast, the subject still has not been settled. Efforts were suggested to assess the proper integration of surgery in radiation therapy in malignant tumors of the thyroid, as well as the appropriate usefulness for radiation therapy, surgery and/or chemotherapy in carcinomas of the lung. In 1960, it was obvious that there were unquestioned difficulties in undertaking experiments in association with radiotherapy: There was the dispersion of human material-a characteristic trend of American medical-working to the disadvantage of radiotherapy since radiotherapy equipment and skill had not followed the patients as operating rooms and skillful surgeons had. Some outstanding institutions which could contribute large numbers of patients to clinical trials were either woefully lacking in equipment or in radiotherapeutic skill or both. Practiced techniques of radiotherapy were far more varied than were surgical procedures. Therefore, it was more difficult to devise standards that would be uniformly followed as the only basis for comparison. Radiotherapeutic experiments were not as easily judged on a short-term basis and their benefits were not as amenable to biometric analysis. 5. Randomized experiments often were conceived to imply the denial of radiotherapy to some patients particularly when radiotherapy, unlike chemotherapy, was curative. From the discussions both at Stone House in 1955 and the subsequent presentation to the Clinical Studies Panel of the National Cancer Institute, the Radiation Study Section of the National Cancer Institute was formed composed of outstanding radiotherapeutic talent in the United States and with a charge to develop cooperative studies. Further, the Radiation Study Section was to support investigations in radiation biology and radiation physics as applied to clinical radiotherapy. The emphasis on communication of new data resulted in a series of conferences, the first of which was held in Highland Park, the second in May, 1960, in Carmel, followed by many others. Group studies for classification of common tumors favoring collective reporting for comparison of results was also a high priority for the Radiation Study Section. Clinical study groups for consideration of national randomized experiments were also necessary. There was at least a Committee on Cancer of the Lung, another on Cancer of the Cervix. Even though protocols had been discussed, clinical trials were not yet under way.

539

Without question, the impact of the meeting at Stone House in 1955 and de1 Regato’s presentation to the Clinical Studies Panel of the National Cancer Institute in 1960 catalyzed the Radiation Study Section but more importantly the radiation oncology community to act. It was this action that led to the creation of the Committee for Radiation Therapy Studies at the suggestion of Shannon then Director of the National Cancer Institute. The first Chairman of that Committee was Fletcher. With the cooperation of the outstanding leaders in radiation oncology, this Committee galvanized the field of radiation oncology. It set the standards for clinical practice ultimately identified and investigated by Kramer through the Patterns of Care Study, it was responsible for the creation of the Radiation Therapy Oncology Group the first Chairman of which was Kramer, it proposed and developed the “Blue Books” which set the standards for radiation therapy practice in terms of resources, facilities, and manpower published first in 1977,6,‘o*’ ‘,I2 the development and publication of the Radiation Research Plans for Radiation Oncology the first in 1976 edited by Kramer9~13~‘4~‘ followed 6 by updates in 1979, 1982, and 1987 (Table 1). The Committee for Radiation Therapy Studies, subsequently the Committee for Radiation Oncology Studies, chaired by first Fletcher, and followed by Kramer, Powers and finally by Brady assumed a new role as the Inter-Society Council for Radiation Oncology chaired by Brady and now by Cox. The Inter-Society Council for Radiation Oncology, represents a joint venture among the major societies in radiation oncology including 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. The Radiation Therapy Oncology Group emerging as a development from the Committee for Radiation Therapy Studies in 1968, funded by the National Cancer Institute in 197 1, has had a major and dramatic impact on coordinating all the efforts in radiation therapy physics, radiation biology, and translating them into cooperative clinical trials having a major and significant impact on Table 1. Contributions of Committee for Radiation Therapy Studies (Committee for Radiation Oncology Studies/ Inter-Society Council for Radiation Oncology) 1. Radiation Therapy Oncology Group initiated in 1968funded by National Cancer Institute in 197 1 2. Radiation Oncology Study Center 1972 3. Patterns of Care Study 1973 4. Particle Program 1976 5. Research Plans 1976, 1979, 1982, 1987 6. “Blue Books” 1972, 1975, 1981, 1986 7. Cooperative Group Outreach 1977 8. Community Clinical Oncology Program 1983

1. J. Radiation Oncology 0 Biology 0 Physics

540

the practice of radiation oncology in the United States. The studies that have emerged from the Radiaton Therapy Oncology Group have changed significantly and have impacted in a major fashion upon the practice of the specialty. More than 13,943 patients have been studied since 1978 in 110 protocols with 53 still active protocols resulting in more than 100 publications3 (Table 2). This has been encouraged and supported by funds from the National Cancer Institute for training and education, for basic scientific support in radiation biology, basic scientific support in radiation therapy physics as well as support through the national cooperative clinical trial study groups in clinical trials, and in assessment of clinical trials in general. Examples of the impact of these types of studies have been felt in many areas of basic and clinical research (Table 2). In the areas of radiosensitizers, 17 Phase II studies were carried out in 591 patients using multiple tumor sites. These were directed toward drug escalation, toxicity and total dose, as well as radiation doses and looked at primarily Metronidazole, Misonidazole, and Desmethylmisonidazole. Seven Phase III studies were carried out in various tumor sites in 2,188 patients showing no advantage with the use of radiation therapy in combination with these radiation sensitizers. However, new radiation sensitizers now are available including SR-2508 which has proceeded through Phase I and II toxicity testing dose escalation studies and is now ready for Phase III studies, as well as IUDR, BSO (a thiol depleting com-

Table 2. Radiation

Therapy Oncology Group

1. Radiation sensitizers Phase II Phase III 2. Radiation protectors Phase I/II 3. Drug and radiation interaction Phase I/II Phase III 4. Time/dose/fractionation Phase I/II Phase III 5. Large field irradiation Phase I/II 6. Isotopic immunotherapy Phase I Phase II Phase III 7. Hyperthermia Phase I/II

8. Particle studies Phase I/II Phase III 9. IORT Phase I/II

Total studies Total patients

No. studies

Patients

17 7

591 2,188

3

230

8 3

1,089 855

12 11

1,739 2,482

9

1,251

1 1 1

66 381 126

4

385

10

760

17

1,670

6

110 13,943

130

September 1988, Volume 15, Number 3

pound) as well as potential investigations in perfluorocarbon compounds. In the field of radiation protectors, WR-272 1 has been pursued in Phase I/II toxicity testing and dose escalation studies in three phase I/II protocols in 230 patients. This sulfhydryl compound is now being pursued in Phase III trials in large volume radiation clinical studies. Major efforts in the Radiation Therapy Oncology Group have been pursued in drug and radiation interaction studies. In this area of Phase I and II studies, eight clinical trials have been pursued in 1,089 patients and three studies of Phase III trials in 855 patients. A major area of investigation is in squamous cell carcinomas of the anus in combination of radiation therapy and 5-l!%orouracil. The data clearly demonstrate definite advantages in the management of this particular group of diseases. In the area of time, dose, fractionation studies, 2,482 patients have been assessed in Phase III trials in 11 studies of continuous radiation therapy programs versus split course radiation therapy programs showing no significant major advantage. Twelve studies, Phase I and II in character, have been carried out in 1739 patients in various studies of altered fractionation. These studies have been directed toward the comparison with standard programs of management comparing hyperfractionation techniques, rapid fractionation, accelerated fractionation, and hypofractionation studies. Within the context of the Phase III clinical trials with altered fractionation techniques has been the study of escalating total radiation dosages in a Phase III setting in using hyperfractionation and accelerated fractionation. Studies of large field irradiation have been carried out in a Phase I/II mode in 125 1 patients in nine studies. Isotopic immunotherapy studies have been carried out in 66 patients in a Phase I mode, 38 1 patients in a Phase II mode, and 126 patients in a Phase III mode. Another area of major investigation is in hyperthermia where 385 patients have been assessed in Phase I/II studies with four clinical protocols. High LET ramains a high priority area for investigation in the Radiation Therapy Oncology Group with a particular emphasis on the neutron generators at the University of Washington; the University of California, Los Angeles; the M. D. Anderson Hospital in Houston; the Fermi Laboratory, Batavia, Illinois; and the Cleveland Clinic. 760 patients have been studied using neutrons in Phase I and II studies, and 1,670 patients in Phase III studies. Other areas of high LET radiations are being pursued in the use of protons at the MIT-MGHHarvard cyclotron in the treatment of choroidal melanomas of the eye where more than 450 patients have been treated, chordomas where more than 100 patients have been treated, and more than 100 patients with tumors in other sites have been treated. The stripped nuclei program at the University of California, Berkeley, has used helium ions primarily in the treatment of choroidal mel-

Gold Medal Address 0 L. W. BRADY

anomas where more than 300 patients have thus far been treated using this technique.4 Intraoperative radiation therapy has now become a major investigative effort under the aegis of the Radiation Therapy Oncology Group. Six clinical trials are currently under way, Phase I and Phase II in character with 130 patients, assessing this technique in at least eight institutions in the United States. Without question, the opportunity for delivering a single fraction of radiation with electron beams of varying energies to identified tumor areas excluding normal tissues has proved its advantage in malignant tumors of the stomach, pancreas, gynecologic tumors, retroperitoneal sarcomas, soft tissue sarcomas, head and neck cancers, etc. The clinical trials managed through the aegis of the Radiation Therapy Oncology Group have had a significant and important impact on multiple disease sites. By improving the potential for local control, the manifestation would be not only on survival without disease but in greater comfort for the patient. This would have particular relevance in tumors of the head and neck, brain, small cell tumors of the lung, large cell tumors of the lung, cervix, etc. The same could be said for primary malignant tumors of the prostate where more than 1,000 patients have now been studied in a randomized setting. Of particular importance is the fact that the Radiation Therapy Oncology Group is the largest single resource for patients who have been treated in clinical trials. The records of more than 30,000 patients are on file at the Statistical Center for the Radiation Therapy Oncology Group offering the single largest pool of patient material in multiple tumor sites in the world for ongoing continued assessment. In general, the Radiation Therapy Oncology Group has demonstrated the impact that local control has on survival. The group has also confirmed the potential for organ preservation using conservation surgery and radiation therapy, or radiation therapy and chemotherapy. Particular examples of this are the data from cancer of the breast where clinical trials have definitively confirmed that conservation surgery and radiation therapy give results that are equivalent to radical mastectomy or modified radical mastectomy,* in carcinomas ofthe anus where 5-Fluorouracil with radiation therapy give results that are equivalent to if not perhaps better than those achieved by surgical management. 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 in the treatment of patient with cancer and to do that with the minimum of complication. Looking to the future, there are a number of areas that are presently in development or imminent for implementation (Table 3). These include the major efforts di-

541

Table 3. Developing areas in radiation oncology 1. Development of dynamic collimators 2. Models for intercomparison among various radiation therapy techniques 3. Data from altered fractionation studies 4. Hypertherrnia data Development of treatment aids 2: Brachytherapy techniques Endoscopic radiotherapy ;: Informational Systems 3-D treatment planning 9. High LET data 10. Better understanding of multimodal plans of treatment 11. MoAB treatment 12. Data from IORT programs 13. More sophisticated statistical techniques 14. More emphasis on organ preservation

rected toward the development of dynamic collimators. The Maughn collimator being developed at the Wayne State University offers the opportunity to construct shaped fields without the necessity for pouring blocks. Ortin is developing a time/dose/volume concept that would allow for intercomparison among radiation therapy techniques. The data from hyperfractionation and altered fractionation studies will lead to major changes in programs of clinical delivery of radiation therapy services. The preliminary data from hyperthermia indicate clearly that in even less than ideal circumstances, hyperthermia in conjunction with radiation therapy improves the potential for local/regional control. The developments in treatment aids will also impact significantly upon the quality of radiation therapy delivery. The reemergence of brachytherapy techniques either as alternatives to external beam radiation therapy or surgery or as an adjuvant in terms of boost to external radiation therapy techniques has been dramatic developments in the last several years and will continue in the foreseeable future. Endoscopic use of brachytherapy sources such as in the lung, intracavitary use of radiation sources for boost as in esophagus, the use of high dose rate additives as well as the availability of better radioisotopes will improve the potentials for brachytherapy techniques. Information systems computer controlled not only in terms of patient data management but also in terms of 3-dimensional treatment planning will have a dramatic impact on improving the potentials for dynamic treatment administration. The development of the data from high-LET radiations clearly indicate certain tumor sites where high-LET radiations alone or in conjunction with conventional radiation therapy techniques lead to better local regional control. The advances and better understanding of combined integrated multimodal programs of management particularly with chemotherapeutic agents will lead to not only better local regional control but also better control of distant disseminated disease. The implementation of monoclonal antibody therapy either labeled with radionuclides or chemotherapeutic

542

1.J. Radiation Oncology 0 Biology 0 Physics

agents or unlabeled has already made significant contributions in cancer management and have the greatest potential to be used as adjuvants in the treatment of patients following definitive primary treatment. And lastly, the better understanding and better implementation of intraoperative radiation therapy techniques will allow the potential for better management of tumors which until this time have been difficult to control. Radiation oncology stands on the threshold of an era of incredible promise and fulfillment. It has been made

September 1988, Volume 15, Number 3

possible by the dedication, leadership, and wisdom that has been brought to the entire field of radiation oncology by dedicated clinicians, clever and careful biologic research investigators and by the major contributions that have been contributed by the radiation therapy physicists. Without question, the promise of the 90s’ is for an ever greater impact on the potential for control of cancer using radiation therapy techniques and with a concomitant reduction in the complication from those techniques.

REFERENCES 1. American Cancer Society Facts and Figures. American Cancer Society, New York, 1987. 2. Brady, L.W., Bedwinek, J.M.: The changing role of radiotherapy. In Breast Disease: Recent Advances in Diagnosis and Treatment, Bonadonna, G. (Ed.). NY, John Wiley & Sons. 1984, pp. 205-227. 3. Brady, L.W., Kramer, S., Wasserman, T.H., Keiser, M., Davis, L.W., Pajak, T.F., Cox, J., Griffin, T., Perez, C.A., Phillips, T.L., Rubin, P., Seydel, H.G.: The radiation therapy oncology group: An outline of clinical research activities. Int. J. Radiat. Oncol. Biol. Phys. (In press) 1988. 4. Brady, L.W., Shields, J.A., Augsburger, J.J., Day, J.L., Markoe, A.M., Castro, J.R., Suit, H.D.: Radiation therapy for malignant intraocular tumors. In Diagnostic Imaging in Ophthalmology, Gonzales, C.F., Becker, M.H., Flanagan, J.C., (Eds.). NY, Springer-Verlag. 1985, pp. 285-3 11. 5. Coutard, H.: Principles of X ray therapy of malignant disease. Lancet 2: l-8,1934. 6. Criteria for Radiation Oncology in Multidisciplinary Cancer Management. Published by the Committee for Radiation Oncology Studies. February 198 1. 7. Curie, P., Curie, Mme P., Bemont, G.: Sur une nouvelle substance fortement radioactive contenue dans la pechblende (note presented by M. Becquerel). Compt. Rand. Acad. Sci. (Paris) 127: 1212-1217,1898. 8. Grubbe, E.H.: Priority in the therapeutic use of X rays. Radiol. 21: 156-162, 1933. 9. The interdisciplinary program for radiation oncology research. Cancer Treat. Symp. 1: 1984. 10. A Proposal for Integrated Cancer Management in the United States: The Role of Radiation Oncology. Published

11.

12.

13. 14.

15.

16. 17.

18.

19.

by the Subcommittee for Revision of the “Blue Book” (1968 report) of the Committee for Radiation Therapy Studies. 1972. A Prospect for Radiation Therapy in the United States. Published by the Subcommittee on Regional Medical Programs of the Committee for Radiation Therapy Studies. 1968. Radiation Oncology in Integrated Cancer Management. Published by the Inter-Society Council for Radiation Oncology. November 1986. Radiation oncology: Research directions 1987. Am. J. Clin. Oncol. ll(3): June 1987. The radiation oncology research program: Recommended research proposals. Int. J. Radiat. Oncol. Biol. Phys. S(5): 335-348,1979. de1 Regato, J.A.: Suggestions for incorporating studies, using radiotherapy, into the clinical studies of the cancer chemotherapy national cancer center. Report to the Clinical Studies Panel of the National Cancer Institute, February 1960. Cancer Chemother. Rep. 7: 47-49, 1960. The research plan for radiation oncology. Cancer 37(Suppl. 2): April 1976. Roentgen, W.C.: Uber eine neue Art von Strahlen. Erste mitteilung sitz gbser physital. Med. Ges. Wursburg. 5: 132-141, 1895. Sheline, G.E., Phillips, T.J., Field, S.B., Brennan, J.T., Raventos, A.: Effects of fast neutrons on human skin. Am. J. Roentgenol. 111: 31-41, 1971. Stone, R.S.: Neutron therapy and specific ionization. Am. J. Roentgenol. 59: 771-785, 1948.