Radionuclide Therapy of Hematologic Disorders Edward B. Silberstein 32p is effective therapy for polycythemia and primary thrombocytosis. The Polycythemia Vera Study Group is comparing radioactive phosphorus with alkylating agents to determine relative efficacy. Less well investigated is the effectiveness of 32p vs. busulfan in chronic granulocytic leukemia. Endolymphatic administration of radiopharmaceuticals may play a role in the therapy of infradiaphragmatic lymphoma. Among the radionuclides that have at times been used in hematology are 32p, tSSAu" 24Na" 7eAs" 89Sr" 52Mb" 54Mn" Sty, gSZr, ssCb, 11lAg, l~

13;I, leSW, and 1921r, As stated, 32p has proven the single most efficacious agent. The hematologic diseases that have been treated include both malignant and benign conditions. Among the malignant conditions are polycythemia vera, agnogenic myeloid metaplasia, thrombocythemia, leukemia, Hodgkin's disease, ancJ multiple myeloma. Hemophilia, and Osler-Weber-Rendu disease are among the benign entities in which the agents have been tried. Polycythemia and thrombocythemia remain those in which the greatest success has been achieved.

AGENTS R ADIOPHARMACEUT1CAL have been part of the hematologist's thera-

panying high- or medium-energy gamma or xrays, which would require isolation of the patient or special shielding for nursing personnel. It should be easily produced in adequate amounts to deliver the desired radiation dose, and have a half-life to permit shipping without undue loss of activity. Its effective half-life must be long enough to deliver the desired dose. With the advent of Ernest O. Lawrence's cyclotron? the production of "artificial" radioactive isotopes became possible as early as 1936. Physical, biologic, and resulting dosimetric considerations concerning 32p (as sodium phosphate) have led to its wide application in the therapy of a variety of hematologic disorders involving bone marrow, liver, and spleen. Emphasis is placed on 32p in this review, since it isthe only radiopharmaceutical currently in common use for the therapy of hematologic disorders.

peutic armamentarium since the introduction of sodium 24 in 1936 and phosphorus 32 the next year for the treatment of chronic leukemia. The use of 32p for polycythemia vera began in 1938. ~ During the next four decades a number of radiopharmaceuticals have been successfully administered to patients with a variety of lymphoproliferative and myeloproliferative diseases. This review will examine the current status of radionuclides in the therapy of several of the disorders encompassed by these two heuristic terms. The use of radionuclides to treat malignant pleural, peritoneal, and joint effusions is discussed elswhere in this seminar. CHOICE OF RADIOPHARMACEUTICALS

Theoretic Considerations The ideal radioactive agent for therapy of hematologic disorders would be taken up only by diseased tissue, where complete decay would occur. The dose delivered to normal tissue would be low enough not to cause physiologic or anatomic alterations. The radiopharmaceutical should emit a beta particle of adequate energy (probably in excess of 500 KeV) without accomFrom the Departments of Medicine and Radiology, Veterans Administration Hospital, University of Cincinnati Medical Center, Jewish Hospital, Cincinnati, Ohio. Supported in part by USPHS Grant CA 10728 from the National Cancer Institute to the Polycythemia Vera Study Group. Reprint requests should be addressed to Edward B. Silberstein, M.D., Radioisotope Laboratory, Cincinnati General Hospital, 234 Goodman Avenue, Cincinnati, Ohio 45267. 9 1979 by Grune & Stratton, Inc. 0001-2998/79/0902~00450100/0 1OO

Phosphate 32: Physical Properties and Pharmacokinetics 32p is a pure beta emitter with maximum energy 1.710 MeV; mean energy 0.6948 MeV. Bremsstrahlung of low energy are also produced in the decay process, which may be used to assay 32p.3,4 The half-life, 14.3 days, poses no difficulties for shipping and storage. The physical characteristics of 32p are summarized in Table 1. Studies of animal and human leukemia indicate that leukemic tissues have greater uptake and exchange of phosphorus than normal tissues, although the total phosphorus content of leukemic and normal tissues is equivalent.5'6 32p, as orthophosphate, is involved in many metabolic pathways. In addition to the damage to DNA caused by the beta particles emitted from 32p, incorporation into DNA, with subsequent decay Seminars in Nuclear Medicine,

Vol. IX, No. 2 (April), 1979

HEMATOLOGIC DISORDERS

101

Table 1. Phosphorus 32 Emission Mean betas/disintegration Maximum energy Mean energy

beta 1.00 1.710 MeV 0 . 6 9 4 8 MeV

Maximum range in tissue

7 8 mm

Mean range in tissue

3 mm

Physical half-life

14.3 days

to s2S and resultant alteration in nucleic acid structure, may be another mechanism by which 32p slows cell proliferation. Within 6 hr-I day of parenteral administration of 32p as sodium orthophosphate, bone concentration exceeds that of muscle, fat, or skin by a factor of 4 to 6: this ratio increases to 6-10 after 3 days. Liver and spleen 32p ratios to muscle, fat, or skin are of the same order of magnitude. 7 Radiation sickness (including gastrointestinal symptoms) has not been described with the 32p doses used for the therapy of hematologic disease. Since the required i.v. dose is approximately 75% of the oral dose, ~ the former route is preferable. However, there is the potential for sloughing of tissue if s.c. infiltration occurs during the i.v. injection. Studies of whole blood and plasma retention of 32p in patients with polycythemia reveal a two-component exponential function, with biologic mean half-lives of 1.7 _+ 0.7 days and 22.5 + 5.9 days for whole blood; 0.8 _+ 0.5 and 20.0 _+ 5.1 days for plasmafl However, wholebody retention curves are monoexponential, with a mean biologic half-life of 39.2 + 4.5 days. 4 Low-Beer et al. found that about 70% of an administered dose decays in the body] The biologic half-life in iliac marrow (approximately 9 days) and sternal marrow (approximately 7 days) do not differ significantly. Dosimetry calculations are complicated by the situation in which two interpenetrating nonequilibrium depositions exist; viz., in trabecular bone and marrow. Also, there is a small contribution to the marrow dose in trabecular bone by 32p in the cortex. Spiers et al. calculated a total absorbed dose to marrow in trabecular bone as approximately 24 rad/mCi injected, with 10 rad/mCi coming from trabecular bone, 13 rad/mCi from marrow, and I rad/mCi from cortical bone. 9 Other investigators have given a range for the 32p dose to bone, marrow, liver, and spleen of from 20 to 50 rad/mCi injected, depending on

such variables as the size of the various compartments and variation in phosphate turnover, s 1o Radionuclides have not been employed to produce severe marrow suppression in the manner that external total body irradiation (usual dose, 1000 rad) has been used before marrow transplantation for hematologic malignancy. ~ With a few exceptions to be noted later, radionuclides, usually 32p, have been employed primarily to suppress hyperproliferative or neoplastic marrow cell lines, with the goal of control rather than cure. Thus, marrow doses of approximately 80-200 rad have been employed. This is within the range of the estimated Do for human marrow, i.e., the radiation dose that will irreversibly inhibit cell division in 63% of cells so treated.~2

32p IN MYELOPROLIFERATIVE DISORDERS Polycythemia Vera Orthophosphate 32 has been an important part of the therapy of polycythemia vera for 40 yr due to its myelosuppressive propertiesJ 3 Its unequivocal efficacy in prolonging median survival to 13-16 yr from onset has been well documented,14 23 but the role of 32p in leukemogenesis in polycythemia vera has been suggested 24 ,,7 as well as possibly increasing the risk of the transition from polycythemia vera to myeloid metaplasia, in retrospective studies. 28'2~ Polycythemia vera may be treated with phlebotomy alone or with myelosuppressive agents, of which 32p was the first. A number of drugs have been employed as well with variable degrees of success, among which are the alkylating agents (e.g., chlorambucil, busulfan), hydroxyurea, procarbazine, pyrimethamine, bromomannitol, and pipobroman. All forms of therapy carry risk as well as benefit, and the optimum form of treatment is still not certain. The P o l y c y t h e m i a Vera S t u d y G r o u p (PVSG), in its initial protocol, has been comparing the results of therapy with 32p or chlorambucil (both using phlebotomy as needed), with phlebotomy alone in a large group of patients. 22 Patient acquisition for randomization to one of these three groups began in 1967. Under study are the effects of the three forms of treatment as they relate to: survival; complications; symptoms; incidence of the transition to "spent" polycythemia; acute leukemia; marrow "hypopla-

102

sia"; myeloid metaplasia and myelofibrosis; cytogenetic abnormalities. The 32p regimen of the PVSG is as follows: 1. Induction is performed with ~2p, 2.3 mCi/sq m of body surface, i.v., with the close not to exceed 5 mCi. 2. Twelve weeks later, if and only if phlebotomy is still required, and less than a 25% decrease in platelet or leukocyte count has occurred, a second dose of 32p is given. This dose may be increased by 25% of the initial dose sequentially, to a final limit of 7 mCi. 32p is not given when the packed cell volume has stabilized without phlebotomy. 3. Retreatment for relapses (packed cell volume in excess of 45%) involves both phlebotomy and 32p given at the previous effective dose. 4. No 32p is given if the platelet count decreases to less than 100,000/~tl or the leukocyte count to less than 3000//zl. Phlebotomy alone is used until these counts return to normal. 5. If hematologic control has not been achieved after 1 yr of 32p treatment, another form of therapy should be attempted, except that 32p is to be repeated at intervals of not less than 12 wk to maintain a platelet count of less than 600,000/ul. (Patients not on protocol might equally well be treated with hydroxyurea or an alkylating agent if there is a suboptimal response

tO 32p.) The PVSG patients treated with phlebotomy alone appear to be at higher risk for thrombotic episodes than the other two groups, which, on the other hand, both have a higher incidence of cancers and leukemic transformations. It must be emphasized that these differences are preliminary findings, and that the majority of patients have been followed for less than 10 years. Thus there are as yet no important overall differences in mortality among the three groups. Due to the prominence of thrombosis in the course of polycythemia, Protocol PVSG-5 has begun a comparison of treatment employing phlebotomy plus two antiplatelet agents, aspirin and dipyridamole, with 32p therapy alone. As a point of historical interest, phosphorus32 baths have also been used successfully to treat intractable pruritus and severe cutaneous infiltrates. 3~

EDWARD B. SILBERSTEIN

Agnogenic Myeloid Metaplasia Radioactive phosphorus has not been widely used in this disorder. Among the many problems which may arise in patients with this disease are thrombocytosis and leukocytosis for which 32p may be given. 31 Experience is so limited in this area that the efficacy of such therapy is unknown, although thrombocytosis should be controllable, as noted in the subsequent discussion.

Primary Thrombocytosis (Thrombocythemia) The myelosuppressive properties of 32p have been successfully used to lower abnormally elevated platelet counts found in this marrow disorder, in myeloid metaplasia-myelofibrosis, undifferentiated myeloproliferative disease, and in chronic granulocytic leukemia. 28'32'33 With thrombocytosis in excess of 1 million platelets ul, the risk of thrombotic and hemorrhagic phenomena may be significant. In addition to 32p therapy, alkylating agents and plateletpheresis have also been employed successfully.33-35 In order to determine the optimal therapy for primary thrombocythemia and the thrombocytosis of the various myeloproliferative syndromes, the PVSG has established a new protocol (PVSG-10), randomizing patients with primary thrombocytosis, myeloid metaplasia-myelofibrosis, myelosclerosis, and other unclassifiable myeloproliferative diseases to treatment with 32p or melphalan (Alkeran). For eligibility, such patients must have a platelet count in excess of 1 million on two separate determinations at least 2 wk apart, not secondary to any other identifiable cause; be 30 yr of age or older; have neither a Philadelphia chromosome nor elevated red cell mass. The marrow must show megakaryocytic hyperplasia. Randomized patients may not have had prior chemotherapy or radiotherapy. These patients receive an initial dose of 2.9 mCi/sq m of 32p i.v. This dose may be increased to 3.6 mCi/sq m if the platelet count still exceeds 600,000/tal in 3 too. Failure to bring the platelet count to less than 600,000/~zl within 6 mo requires, in protocol PVSG-10, a switch to melphalan. With a response to 32p, radioactive phosphorus is continued to keep the platelet count less than 600,000//zl. A 25% increase in

HEMATOLOGIC DISORDERS

the -~2Pdose is permitted as long as no single dose exceeds 7 mCi. The interval between treatments is not to be less than 3 mo, and the total dose is not to exceed 35 mCi. To date, the average decreases in platelet count and the survival from both forms of therapy are not significantly different, but the number of patients is still small. The required 32p doses appear quite variable, and prolonged remissions have been noted after a single 32p injection. THE L E U K E M I A S

In 1936 24Na as sodium chloride became the first radionuclide employed for leukemia therapy.36 Some improvement from this treatment was apparent, 37'38 but this was shown to be comparable to total body radiation, 39as might be predicted from its wide tissue distribution. Leukemia was the first disease for which 32p was employed, ~ and it has been successfully administered in many medical centers to decrease elevated leukocyte counts in chronic granulocytic and lymphocytic leukemia, t3'4~ More recently, alkylating agents have largely replaced 32p for treatment of the chronic leukemias. Alkylating agents do appear clearly superior to 32p for chronic lymphocytic leukemia. 46 However, there is still no study that this reviewer or others 47'48 have found in which patients were randomized to either an alkylating agent or 32p for chronic granulocytic leukemia (CGL). A recent claim that several schedules of chemotherapy gave better results than 32p for CGL involved a comparison of data from patients who received splenic irradiation or 32p, published between 1951 and 1968, with several series using chemotherapy, published from 1968 to 1973. 49 However, too many improvements in medical care have taken place during the years to permit any valid comparisons of studies separated in time by decades. Another study, published in 1961, suggested that the median survival of patients given busulfan is "at least as long as that of comparable groups treated by radioactive phosphorus or x-ray (median 32 to 41~/2 months) excepting Osgood's 5o combined myelocytic and lymphocytic leukemia group". 5~ The heterogeneity of the patients and therapies being compared make such statements hard to

103

interpret and apply clinically. At this time, the PVSG has no protocol addressing the relative efficacy of 32p and chemotherapy in chronic leukemias. Osgood has provided data that chronic granulocytic leukemia is approximately twice as radioresistant as chronic lymphocytic leukemia, and that I mCi of 32p given i.v. is equivalent in biologic effect to 15 rad of total-body x-ray irradiation given by his technique. 42 Intravenous colloidal 198Au was successfully employed to treat chronic granulocytic leukemia in the early 1950s, 52 but this material is no longer available commercially. In the primary therapy of acute leukemia, 32p has little or no value. 13'53'54 lntrathecal 198Au colloid has been employed along with either cerebrospinal axis radiotherapy or intratheca[ methotrexate in the successful prophylaxis of central nervous system leukemia and non-Hodgkin's lymphoma. 55 In a brief summary by this same group, 56 the efficacy of intrathecal J9SAu alone appeared promising. Radioactive arsenic, as sodium arsenite As 76, in doses up to 90 mCi, has been administered to patients with chronic leukemias, leading to remissions comparable to those produced by 32p, roentgen therapy, or urethane. Its short half-life, 26.5 hr, and energetic gamma emissions make shipping, preparation, administration, and radiation-safety protection considerably more difficult than with 32p.57 OTHER LYMPHOPROLIFERATIVE DISORDERS

Systematic Phosphorus 32 Systemic phosphorus 32 as sodium phosphate has also been employed in Hodgkin's disease, a wide variety of non-Hodgkin's lymphomas, multiple myeloma, and mycosis fungoides-either without effect or with much less therapeutic efficacy than focal irradiation. 5s There is a report of an uncontrolled study of 1 1 myeloma patients, wherein 32p decreased or relieved pain in all subjects. 59 One group obtained some amelioration of bone pain with 32p and the boneseeking 89Sr, but did not feel that 89Sr added to the 32p effect, which was equivalent to focal x-ray therapy. 6~ Others believe 32p is of definite value in the palliation of the bone pain of myeloma. 61

104

Intravenous Colloid Gold 198 In addition to its use in intracavitary therapy (discussed elsewhere), i.v. 198Au, as in colloidal suspension, was introduced some 30 yr ago to deliver significant radiation doses to diseased reticuloendothelial tissue. 5z62 More recently, Hodgkin's disease patients with laparotomydocumented splenic and/or hepatic involvement have been treated with 25-30 mCi of colloid 198Au in fractionated doses, combined with total lymphoid and external liver irradiation to deliver 2500 rad to the liver--a dose below the threshold for radiation hepatitis. 63 Thrombocytopenia was moderate to severe in slightly more than 50% of patients treated. A few patients were reported disease-free 2-5 yr after therapy, but the regimen has not been widely adopted and ~98Auis no longer available commercially in the United States, as noted previously.

Other Radionuclides in Colloidal Form An i.v. mixture of 52Mn and 54Mn as manganese dioxide colloid was employed approximately 30 yr ago for irradiation of the reticuloendothelial system in lymphoma, Hodgkin's disease, and lymphocytic leukemia.64 Insoluble chromic phosphate, also concentrating selectively in the liver and spleen, was also used for this purpose, 65~67 as were colloids of several fission products: 91y, 9SZr ' and 95Cb.67'68 198Au 198 replaced these materials, since the latter has a higher splenic concentration.69 Interstitial infiltration of lymph nodes with insoluble gold colloid has successfully decreased node size. ~ A g has also been suggested for this purpose. 7~ Chromic phosphate P 32 as a colloidal suspension is still commercially available, but i.v. injection is not authorized by the FDA, according to Mallinckrodt Technical Information Services. These colloidal radiopharmaceuticals have all been replaced by combination chemotherapy and focal teletherapy.

EDWARD B. SILBERSTEIN

tissue appeared histologically normal. 71'72 Such agents might also achieve selective lymphatic destruction in lymphoma, although no human studies have been reported.

Colloidal Tungsten (ISSw) Trioxide A colloidal form of 185W injected into the mammalian splenic parenchyma, with prevention of recirculation by a vascular clamp for 30 min, has provided an interesting model for continued irradiation of circulating lymphocytes, with resultant lymphocytopenia and mild immunosuppression. 73 This conceivably could be another technique for therapy of lymphoma.

Endolymphatic Radionuclide Therapy A more specific route of delivery of radiation dose to diseased lymphatic tissue is available. Intralymphatic administration of radiopharmaceuticals such as Ethiodol-I 131 or EthiodoI-P 32 can deliver radiation doses of 10,000-100,000 rad to the inguinal and iliac nodes, with the dose decreasing higher in the lymphatic chain. 74'7s Pulmonary doses have not been calculated but would be expected to be substantial, since the lymphangiographic material eventually passes through the lungs. Ariel suggests the utility of endolymphatic therapy, especially with stage I or II infradiaphragmatic lymphoma, based on his results with the technique. 74 198Au and 32p colloids administered via the endolymphatic route also cause lymphocytopenia and immunosuppression without pathologic changes of the spleen or liver. The whole-blood dose can be limited to 0.1 rad, whereas 1 mCi of 198Au can deliver up to 35,000 rad to the iliac nodes; or 150,000 rad may be received in these nodes with 0.2 mCi of colloid 32p.76 Finally, it has been suggested that therapeutic doses of radiation might be delivered by endolymphatic or i.v. administration of a beta emitter bound to an immunoglobulin with specificity for tumor antigens.77-81

Protoporphyrin t~ One group has employed ~~ rin, administered i.v., to obtain selective radiation destruction of lymphatic tissues (nodes and spleen) to control homograft rejection. The liver received the same dose as the lymph nodes sampled with this technique, although hepatic

NONMALIGNANT HEMORRHAGIC DISORDERS

Hemophilia The use of radionuclides such as colloid 198Au or chromic phosphate 32p in treatment of intraarticular hemorrhage is discussed elsewhere. 82

HEMATOLOGIC DISORDERS

Osler~ Weber-Rendu Disease

Brachytherapy with iridium 192 has ameliorated the severe epistaxis in Osler-WeberRendu disease without the nasal perforation problem that is seen with radium. ~3 REFERENCES

1. Lawrence JH: Personal communication, 20 October 1978. 2. Lawrence EO, Cooksey D: On the apparatus for the multiple acceleration of light ions to high speeds. Phys Rev 50:1131 1140,1936 3. Zimmer AM, Silverstein EA, Holmes RA: Assay of 32P-sodium phosphate using a commercial dose calibrator. J Nucl Med 17:404 405, 1976 4. Silberstein EB, Williams CC, Thomas SB: Assay of 32p-sodium phosphate, J Nucl Med 18:98, 1977 5. Lawrence JH, Scott KG, Turtle LW: Studies on leukemia with the aid of radioactive phosphorus, lnt Clin 3:33 58, 1939 6. Lawrence JH, Tuttle LW, Scott KG, et al: Studies on neoplasms with the aid of radioactive phosphorus. I. The total phosphorus metabolism of normal and leukemic mice. J Clin Invest 19:267 271, 1940 7. Low-Beer BVA, Blais RS, Scofield NE: Estimation of dosage for intravenously administered 32p. Am J Roentgenol 67:28 41, 1952 8, Mallinckrodt Nuclear, Technical Product Data, Sodium Phosphate P32, February 1975, p 2 9. Spiers FW, Beddoe AH, King SD, et al: The absorbed dose to bone marrow in the treatment of polycythemia by 32p, BrJ Radiol 49:133-140, 1976 10. International Commission on Radiological Protection. Protection of the Patient in Radionuclide Investigations. ICRP Publication No. 17, Pergammon, Oxford, 1971, p 64 11. Thomas ED, Buckner CD, Rudolph RH, et al: Allogeneic marrow grafting for hematologic malignancy using HL-A matched donor-recipient sibling pairs. Blood 38:267 287, 1971 12. Senn JS, McCul/och EA: Radiation sensitivity of human bone marrow cells measured by a cell culture method. Blood 35:56-60, 1970 13. Lawrence JH: Preliminary report on a new method for treatment of leukemia and polycythemia. Radiology 35:5160, 1940 14. Stroebel CF: Current status of radiophosphorus therapy, Proc Staff Meet Mayo Clin 29:1-4, 1954 15. Reed C: Polycythemia rubra vera. Med J Aust 2:654658, 1965 16, Szur L, Lewis SM: The haematological complications of polycythemia vera patients treated with radioactive phosphorus. Br J Radiol 39:122-130, 1966 17. Duggan HE: Polycythemia rubra vera and radioactive phosphorus-90 patients. J Can Assoc Radiol 17:4-9, 1966 18. Watkins PJ, Fairly GH, Scott RB: Treatment of polycythemia vera. Br Med J 2:664-666, 1967 19. Harman JB, Ledlie EM: Survival of polycythemia vera patients treated with radioactive phosphorus. Br Med J 2:146-148, 1967

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20. Osgood EE: The case for 3zp in treatment of polycythemia vera. Blood 32:492-499, 1968 21. Campbell A, Emery EW, Godlee JN, et al: Diagnosis and treatment of primary polycythemia. Lancet l:1074 1077, 1970 22. Wasserman LR: The treatment of polycythemia vera. Semin Hematol 13:57-78, 1976 23. European Organization for Research on the Treatment of Cancer: Treatment by radiophosphorus versus busulfan in polycythemia vera: recent results. Cancer Res 62:104109, 1977 24. Tinney WS, Hall BE, Giffin HZ: The prognosis of polycythemia vera. Proc Staff Meet Mayo Clin 20:306, 1945 25. Modan B, Lilienfeld AN: Polycythemia vera and leukemia: role of radiation. Treatment study of 1222 patients. Medicine 44:305-344, 1965 26. Landaw SA: Acute leukemia in polycythemia vera. Semin Hematol 13:33-48, 1976 27. Tubiana M, Flamant R, Attie E, et al: A study of hematological complications occurring in patients with polycythemia vera treated with ~2p. Blood 32:536-548, 1968 28. Silverstein MN: Postpolycythemia myeloid metaplasia. Arch Intern Med 134:113, 1974 29. Silverstein MN: Myeloproliferative diseases. Postgrad Med 61:206-210, 1977 30. Wasserman LR: Personal communication, 26 October 1978 31. Ward HP, Block MH: The natural history of agnogenic myeloid metaplasia (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine 50:357-420, 1971 32. Preston FE, Emmanuel IG, Winfield DA, et al: Essential thrombocythemia and peripheral gangrene. Br Med J 3:548-552, 1974 33. Hoagland HC, Perry MC: Thrombocythemia (thrombocylosis). JAMA 235:2330-2331, 1976 34. Coleman RW, Sievers CA, Pugh RP: Thrombocytopheresis: a rapid and effective approach to symptomatic thrombocytosis. J Lab Clin Med 68:389 399, 1966 35. Laszlo J: Myeloproliferative disorders (MPD). Myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia. Semin Hematol 12:409-432, 1975 36_ Hamilton JG, Stone RS: The intravenous and intraduodenal administration of radiosodium. Radiology 28:178, 1937 37. Thygesen JE, Videback A, Villaume I: Treatment of leukemia with artificial radioactive sodium; preliminary report. Acta Radiol (Stockh) 25:305-316, 1944 38. Lindgren E: Ver suche mit radioactiven Isotopen bei Leukamiebehandlung. Acta Radiol (Stockh) 25:614-624, 1944 39. Evans TC, Quimby EH: Studies on effects of radioactive sodium and of roentgen rays on normal and leukemic mice. Am J Roentgenol 55:55-66, 1946 40. Reinhard EH, Neely CL, Samples DM: Radioactive phosphorus in the treatment of chronic leukemias: Long term results over a period of 15 years. Ann Intern Med 50:942958, 1959

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41. Osgood EE: Treatment of chronic leukemias. ,i Nucl Med 5:139-153, 1964 42. Osgood EE: The relative dosage required of total body x-ray vs. intravenous 32p for equal effectiveness against leukemic cells of the lymphocytic series or granulocytic series in chronic leukemia. ,i Nucl Med 6:421~,32, 1965 43. Benassi E, Torretta A: Cenni sull 'impiego dei radioisotopi nella diagnosi e nella cure delle poliglobulie e delle leucemie. Minerva Med 59:1752-1762, 1968 44. Arini E: El empleo terapeutico del 32p en ciertas hemopatias. Medicina 28:61-70, 1968 45. Silver RT: The treatment of chronic lymphocytic leukemia. Semin Hematol 6:344-350, 1969 46. Huguley CM: Survey of current therapy and of problems in chronic leukemia, in Leukemia-Lymphoma. Chicago, Year Book, 1970, p 317 47. King ER, Sharpe AR: Present status and future prospects of radioisotopes in the diagnosis and therapy of cancer. Proc Natl Cancer Conf 6:301-326, 1970 48. Chaudhuri TK: Role of 32p in polycythemia vera and leukemia, in Spencer, RP (ed): Therapy in Nuclear Medicine. New York, Grune & Stratton, 1978, pp 223-235 49. Sokal JE: Evaluation of survival data for chronic myelocytic leukemia. Am J Hematol 1:493-500, 1976 50. Osgood EE, Seaman ALl: Treatment of the chronic leukemias: results of therapy of 163 patients by titrated regularly spaced total body radioactive phosphorus or roentgen irradiation. JAMA 150:1372, 1952 51. Haut A, Abbott WS, Wintrobe MM, et al: Busulfan in treatment of chronic myelocytic leukemia: the effect of long term intermittent therapy. Blood 17:1, 1961 52. Andrews GA, Tyor MP: Early results of the treatment of chronic granulocytic leukemia with intravenous gold-198. J Lab Clin Med 42:777, 1953 53. Reinhard EH, Moore CV, Bierbaum OS, et al: Radioactive phosphorus as a therapeutic agent. A review of the literature and analysis of the results of treatment of 155 patients with various blood dyscrasias, lymphomas, and other malignant neoplastic diseases. ,i Lab Clin Med 31:107-218, 1946 54. Wasserman LR, Rashkoff IA, Yoh TF: The use of radioactive and stable isotopes in hematology. ,i Mt Sinai Hosp 17:1037-1047, 1951 55. Metz O, Blau H,I, Weinmann G, et al: Zum gegenw~.rtigen Stand der ZNS-Prophylaxe mit 198-Goldkolloid und 60-Telekobalt bei akuten Leuk~imien und Non-Hodgkin-Lymphomen im Kindesalter. Dtsch Gesundheitsm 31:2472-2476, 1976 56. Metz O, Stall W, Unverricht A, et al: 5-,iahre Meningosis-Prophylaxe mit Radiogold bei Leukamie im Kindesalter. Radiol Diagn (Berl) 19:113-114, 1978 57. Carpender JWJ, Jacobson LO: Medical uses of radioisotopes, in Portmann UV (ed): Clinical Therapeutic Radiology. New York, T. Nelson & Sons, 1950, pp 697-709 58. Diamond HD, Craver LF, Woodard HQ: Radioactive phosphorus in the treatment of malignant lymphoma, plasma cell myeloma, Ewing's sarcoma, and osteogenic sarcoma. Cancer 10:143-150, 1957 59. Zorrilla Dendarieta JM, Martinez Rodriguez ,IL, Estenoz Alfaro JM: Tratamiento con 32p del sintoma dolor en el mieloma. Rev Clin Esp 137:253-255, 1975

EDWARD B, SILBERSTEIN

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HEMATOLOGIC DISORDERS

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Radionuclide therapy of hematologic disorders.

Radionuclide Therapy of Hematologic Disorders Edward B. Silberstein 32p is effective therapy for polycythemia and primary thrombocytosis. The Polycyth...
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