Radioactive Isotopes and Nuclear Radiations in the Treatment of Cancer* JOHN H. LAWRENCE AND CORNELIUS A. T0BIAs (Donner Laboratory and Donner Pavilion, University of California, Berkeley, Calif.) It is now @20years since we began to use arti shipments is for medical use, and one-third of ficially produced radioactive isotopes in cancer re these shipments are for cancer therapy. For in search and in medical research. Actually, our first stance, there are 50 medical groups in the United therapeutic trials were in 1936. In the early days States using radioactive colloidal gold and radio the hope was that at the end of @0years one could active colloidal chromic phosphate for interstitial report outstanding examples of selective localiza infiltration in various types of cancer, such as tion of radioactive compounds in neoplastic tissue, prostatic, uterine, and bronchogenic. Two hundred making it possible to give the tumor tissue many fifty groups are using radioactive gold, chromic times more irradiation than the surrounding, nor phosphate, and yttrium colloids in the treatment mal tissues. of cancer metastasized to the pleural and perito Up to the present moment, investigations with neal cavities. There are 400 groups using iodine only two radioactive isotopes have given us impor 181 in the diagnosis and treatment of hyperplastic tant therapeutic applications in hyperplastic and and neoplastic thyroid disease and 889 groups neoplastic diseases through selective localization. using @32forthe treatment of polycythemia vera These are radiophosphorus in the treatment of and chronic leukemia. During 1954 there were polycythemia vera and radioiodine in the treat over 5,000 shipments of radioactive iodine from ment of the thyroid hyperplasia of Grave's disease Oak Ridge to individual users, over @,500ship and in the palliative treatment of certain thyroid Inents of radioactive phosphorus, and 6@ ship cancers. However, one who has worked in the field ments of radioactive gold. At the present time from the beginning and who is asked to sum up his there are 30 cobalt teletherapy units in the United experiences can't help saying that the therapeutic States in use for external irradiation therapy of achievements have been disappointing; but even cancer with high energy gamma rays, and 50 more in the early days we believed that the greatest are being planned (1).' contribution of radioactive isotopes in the field Most of the isotopes which have been used in of medical and cancer research would lie in tracer the therapy of hyperplastic or neoplastic diseases applications, and we have devoted most of our in the form of internal, intracavitary, interstitial, energies to the latter. contact, tele, or fission radiation are listed in Even though the achievements in prolongation Chart 1 in the order of increasing atomic number. of life and cures in cancer have not been great so Early work by Kruger in this laboratory 15 far, one should not dismiss too lightly the con years ago (@5) and by Zahl at al. (59), followed by tributions of artificial radioactivity and nuclear the uranium fission experiments by Tobias at al. radiations in cancer therapy. The clinician should (55), more recently has led to the trial of boron-lO not underestimate the importance of relief from in the treatment of brain tumors, particularly glio pain and extension of comfortable life, and here blastomas, the radiation being derived from the their value is well established. fission of the boron nuclei after slow neutron cap The importance of the products of nuclear phys ture (7). Kruger bathed tumor slices in boric acid ics in cancer therapy is pointed up by the fact that solution in vitro and then irradiated them with demands for radioactive isotopes in medical and slow neutrons, causing fission of the boron nuclei biological research have risen rapidly in the past 10 into lithium and alpha particles. The ionization ob years. The shipments of radioactive isotopes from tained is relatively densely localized, the particles Oak Ridge National Laboratory have risen from traveling about one cell diameter (55). After borax less than 500 in 1946 to almost 1@,000 in 1954. containing boron-lO was injected intravenously Seventy per cent of the total dollar value of all into patients with brain tumors who were then ex posed to soft neutrons from the atomic pile, Farr, * Presented as part of the Symposium on Radioactive Iso topes and Cancer at the meeting of the American Association Sweet at al. (7, 13) have been able to deliver a few of Cancer Research in San Francisco, April 16, 1955. Papers ‘Atthe International Conference @nthe Peaceful Uses of presented by David M. Greenberg and by Jacob Furth have Atomic Energy held in Geneva in August, 1955, the author appeared in the August, 1955, and the January, 1956, issues of learned from Professors Modestov and Fateyeva that there are Cancer Research, respectively. 150 such units now in operation in the Soviet Union. 185 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1956 American Association for Cancer Research. 186 Cancer Research hundred roentgens to the tumor tissue by such fis palliative treatment of advanced cancer of the sion energy, but this is probably insufficient to give bladder, but the survival time is not available for real therapeutic effect. Pathological studies of eight a large series of patients (58). The beta- and gam of the first ten patients treated at Brookhaven ma-emitting isotope Na24 has also been tried in the showed changes suggestive of irradiation effects in treatment of chronic leukemia, but the method has three patients; however, large areas of viable tu not found wide usage, since there is no selective mor were found in all cases (13). More recent in localization of sodium. vestigations by Kruger have shown that the con The first example of a successful application of a centration of boron in the boundary between nor radioactive isotope in therapy was the treatment mal and tumor tissue in glioblastoma multiforme of polycythemia vera with @32•Enoughexperience tumors in mice can be increased by injection of has been gained over the past @20yearsto allow one SOME OF THE THERAPEUTIC USES OF RADIOACTIVE ISOTOPES Glioblastoma multiforme Bladder carcinoma Polycythemia, chronic leukemias, breast cancer Control of oscites and pleural effusion in metastatic Deritoneal and aleural carcinoma .@ carcinoma, cervix carcinoma, bronchogenic carcinoma erkeratosis, basal cell carcinoma, squamous cell carcinoma ‘iancarcinoma @ carcinoma, naso-pharynx tumor, maxillary tumor, I I•.' esophaqeal carcinoma, uterine body carcinoma 1 1 carcinomaDeep-seatedcarcinoma, cervix carcinoma, bronchogenic —@Bladder tumors :...Prostate carcinomaOvarian carcinoma5r90Pterygium, vernal conjunctivitis, vascularization of cornea Hepatomegaly and splenomegaly in advanced leukemia II — — Thyroid cancer angina pectoris congestive heart failure. hyperthyrodism Hepatomegaly and splenomegaly in advanced leukemia J 1 Control of ascites and pleural effusion in metastatic carcinoma I I Prostate carcinoma, cervix carcinoma, bronchogenic carcinoma Other isotopes used in therapy: Calcium, Chromium, Gallium, Arsenic, Thulium, Lanthanum, Ceseum, Astatine, Ruthenium CHART 1 .—Some therapeutic applications of radioactive isotopes Evans Blue dye containing boron-lO in the mole to say that the condition can be satisfactorily con cule (@6). Although the localization of the radio trolled by @82(@9).The survival of patients with isotope achieved by use of the dye is 30 times that polycythemia treated by @32isabout equal to that obtained after injection of boron-lO as borax solu in cases of pernicious anemia treated by liver or tion, the localization is greatest at the brain-tumor vitamin B@2and diabetes mellitus treated by in interface and is not uniformly distributed through sulin (Chart @),and is superior to any increased out the tumor tissue. Consequently, there is still survival rate yet achieved in such cancers as insufficient localization in tumor cells to provide breast or prostatic cancer with newer methods of the needed radiation. However, the use of such therapy (Chart 3). The median survival in pa boron-containing dyes should be explored. If fis tients with polycythemia vera is 14 years, com sionable material can be synthesized into com pared with a survival of approximately @0yearsfor pounds that will give great selective localization in an age-matched group of the general population. neoplastic tissue, there is little doubt that great Since 1936, when @32wasfirst used in the treat therapeutic benefit can result. ment of chronic leukemia (30), thousands of pa Sodium-@4 and bromine-8@ have been used in tients have been treated. As shown in Chart 3, the form of fluid instillation into the bladder for approximately 50 per cent of the patients with Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1956 American Association for Cancer Research. LAWRENCE AND ToBrJ1s—Radioactive Isotopes in the Treatment of Cancer 187 chronic lymphatic leukemia treated by P@ will is pipetted onto it, and the plaque is then applied survive over 5 years (@8). This is somewhat better directly to the lesion. In the case of basal-cell car than the 8urvival in 1,600 cases treated by conven cinoma, a dose of 34,000—36,000 rep is delivered to tional methods reported in the literature review by the surface, and @0,000—@,500repdelivered to the Osgood (81). first millimeter depth in a period of 48 hours. This Between 1985 and 1940, in the early days of the method is producing results equal to those of any radioisotope work, we attempted to treat a group other of the more conventional methods now in use of patients with breast cancer and prostate cancer for the treatment of superficial skin cancer. metastatic to bone by means of intravenous or Radiophosphorus as colloidal chromic phos oral administration of @32orSr89 (@7, 80, 40). It phate (@1),first used by Jones et at. (fl), as well as had been demonstrated that strontium, like cal cium, localized to a high degree in bony tissue with less uptake than P@ in soft tissue.