use of radioactive phosphorus in haematology

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Blootl Rrvitw,s ( 1997) 11, 146-153 11 1997 Pearson Professional Ltd Haematological oncology Use of radioactive phosphorus in haematology B. E. Roberts, A. H. Smith Following the development of the cyclotron in 1932,radio-isotopes became available for use in medicine both as tracer substances and therapeutic agents. The father of nuclear medicine, Dr J. H. Lawrence, pioneered their use in a range of disease statesand found that radio-isotopes were of enormous value in the diagnosis and treatment of haemopoetic disease, particularly the myeloproliferative disorders. Radioactive phosphorus 32P emergedas the radio-isotope of choice for the myelosuppressive treatment of myeloproliferative disorders. This article also describesthe use of radio-isotopes in the treatment of other disorders: chronic myeloid leukaemia, chronic lymphocytic leukaemia and myeloma, work that is now largely forgotten. All myeloproliferative disorders may evolve without treatment into myelodysplastic syndrome or blast-cell transformation. It is accepted that life is prolonged in myeloproliferative disorders treated with 3’Por alkylating agents,yet both are leukaemogenic. The ideal form of treatment for polycythaemia vera is unknown and will remain so, for patients with this disorder often outlive their physician and achieve90% of normal life expectation. “P remains the treatment of choice for elderly patients with polycythaemia Vera. Radio-isotopes for use in medicine became available in 1934, some 38 years after the discovery of X-rays by Riintgen in 1896. They were first made in quanti- ties sufficient for medical work from the cyclotron developed by Ernest Lawrence and colleagues in Berkeley, California in 1932. The exploitation of the use of isotopes in medicine was made by a team of workers in California associ- ated with the cyclotron project led by John Lawrence, brother of Ernest. It is generally acknowledged that John Lawrence was the founding father of nuclear medicine as a discipline and much of his pioneering work was in the field of haematology. Lawrence used radio-isotopes as both tracer substances and as a form of therapeutic irradiation.’ The agent Lawrence used most commonly for therapy was radioactive phosphorus 32P Dr B. E. Roberts, Department of Haematology; Dr A. H. Smith, Department of Medical Physics, General Infirmary. Leeds LSI 3EX. UK - 146 RADIOACTIVE PHOSPHORUS: THE THERAPEUTIC AGENT Current knowledge 32P is a pure beta-emitter of maximum energy 1.71 Mev. with a mean range in tissue of 3 mm and a maximum of 8 mm. It has a half-life of 14.3 days. Administered intravenously as sodium ortho- phosphate, it is taken up preferentially by bone, spleen and liver. Within 6-24 h of parenteral adminis- tration of ?:P as sodium orthophosphate, bone con- centration exceeds that of muscle, fat or skin by a factor of 4-6; this ratio increases to 610 after 3 days. Liver and spleen ‘*P ratios to muscle, fat or skin are of the same order of magnitude.’ Initially, “P is selec- tively concentrated in the mitotically active cells in the bone marrow and, within the first few days, is incor- porated in the calcium phosphate of the bone lying adjacent to the endosteum. The effective dose of 32P for adults is given by the International Commission on Radiological Protection

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  • Blootl Rrvitw,s ( 1997) 11, 146-153 11 1997 Pearson Professional Ltd

    Haematological oncology

    Use of radioactive phosphorus in haematology

    B. E. Roberts, A. H. Smith

    Following the development of the cyclotron in 1932, radio-isotopes became available for use in medicine both as tracer substances and therapeutic agents. The father of nuclear medicine, Dr J. H. Lawrence, pioneered their use in a range of disease states and found that radio-isotopes were of enormous value in the diagnosis and treatment of haemopoetic disease, particularly the myeloproliferative disorders. Radioactive phosphorus 32P emerged as the radio-isotope of choice for the myelosuppressive treatment of myeloproliferative disorders. This article also describes the use of radio-isotopes in the treatment of other disorders: chronic myeloid leukaemia, chronic lymphocytic leukaemia and myeloma, work that is now largely forgotten. All myeloproliferative disorders may evolve without treatment into myelodysplastic syndrome or blast-cell transformation. It is accepted that life is prolonged in myeloproliferative disorders treated with 3P or alkylating agents, yet both are leukaemogenic. The ideal form of treatment for polycythaemia vera is unknown and will remain so, for patients with this disorder often outlive their physician and achieve 90% of normal life expectation. P remains the treatment of choice for elderly patients with polycythaemia Vera.

    Radio-isotopes for use in medicine became available in 1934, some 38 years after the discovery of X-rays by Riintgen in 1896. They were first made in quanti- ties sufficient for medical work from the cyclotron developed by Ernest Lawrence and colleagues in Berkeley, California in 1932.

    The exploitation of the use of isotopes in medicine was made by a team of workers in California associ- ated with the cyclotron project led by John Lawrence, brother of Ernest. It is generally acknowledged that John Lawrence was the founding father of nuclear medicine as a discipline and much of his pioneering work was in the field of haematology. Lawrence used radio-isotopes as both tracer substances and as a form of therapeutic irradiation. The agent Lawrence used most commonly for therapy was radioactive phosphorus 32P

    Dr B. E. Roberts, Department of Haematology; Dr A. H. Smith, Department of Medical Physics, General Infirmary. Leeds LSI 3EX. UK

    -

    146

    RADIOACTIVE PHOSPHORUS: THE THERAPEUTIC AGENT

    Current knowledge

    32P is a pure beta-emitter of maximum energy 1.71 Mev. with a mean range in tissue of 3 mm and a maximum of 8 mm. It has a half-life of 14.3 days.

    Administered intravenously as sodium ortho- phosphate, it is taken up preferentially by bone, spleen and liver. Within 6-24 h of parenteral adminis- tration of ?:P as sodium orthophosphate, bone con- centration exceeds that of muscle, fat or skin by a factor of 4-6; this ratio increases to 610 after 3 days.

    Liver and spleen *P ratios to muscle, fat or skin are of the same order of magnitude. Initially, P is selec- tively concentrated in the mitotically active cells in the bone marrow and, within the first few days, is incor- porated in the calcium phosphate of the bone lying adjacent to the endosteum.

    The effective dose of 32P for adults is given by the International Commission on Radiological Protection

  • Radioactive ohosohorus in haematologv 147

    (ICRP) as 2.4 mSv per MBq administrated, with the absorbed dose to bone surfaces and marrow as 11 mGy/MBq. These calculations are based on the metabolic model from ICRP Publication 53. which assumes that a fraction of 0.3 of the injected activity goes to mineral bone and to be permanently retained, and 0.70 is distributed in soft tissue. Activity dis- tributed in soft tissue is assumed to be excreted with half-times of 12 h, 2 days, and 19 days.

    Studies with whole blood and plasma retention of P in nine patients with polycythaemia. reported by Spiers et al, revealed a two-compartment exponential function, with biological mean half-lives of 1.7 f 0.7 days and 22.5 f 5.9 days for whole blood; 0.8 + 0.5 and 20.0 f 5.1 days for plasma. The biological half-life in iliac marrow (approx 9 days) and sternal marrow (approx 7 days) did not differ significantly. However, whole-body retention curves measured using a whole- body radiation counter were found to be monoexpo- nential. with a mean biological half-life of 39.2 f 4.5 days. This is in broad agreement with the value of 49 days given by Seltzer.

    Spiel-s et ali calculated a total absorbed dose to marrow in trabecular bone as approximately 6.5 mGy per MBq injected, with 2.7 mGy per MBq from trabecular bone, 3.5 mGy per MBq from marrow and 0.3 mGy per MBq from cortical bone. These dosimetry calculations took allowance for the existence of the two interpenetrating nonequilibrium depositions (in marrow and trabecula bone) and the small contribu- tion to the marrow dose in trabecula bone by P in the cortex.

    Other investigators have given a range for the P dose to bone, marrow, liver and spleen from 5.4 to 13.5 mGy per MBq injected, depending on such variable as the size of the various compartments and variations in phosphate turnover.

    Protocols determining the quantity of P adminis- trated vary, but usually range between 110 MBq and 220 MBq. Berk et al used 100 MBq m in the PVSGOS protocol, with a limit of 185 MBq initially. If this was not sufficient at 3 months, it was increased by 25%1, with a further increase of 25% if improve- ment was not observed over the next 3 months; the maximum dose suggested was 260 MBq.

    The use of radioactive phosphorus in the treatment of polycythaemia Vera

    One of the diseases Lawrence chose to treat with radio-isotopes was polycythaemia Vera. This disorder was first described by Vaquez in 1892 and subse- quently by Osler in 1903. Osler, describing a further case at a Clinical Pathological Conference at the John

    ANALYSIS OF TREATMENT

    Fig. 1 The range of isotopes used by Lawrence et al: (Reproduced with permission from I).

    Radcliffe Hospital in Oxford in 1908, stated that the patient would be treated with inhalations of oxygen and radiotherapy to the spleen. Thus, one of the first cases of polycythaemia vera described in the literature was treated with radiotherapy and it became accepted as one of a range of therapies for this disorder.

    It was logical, therefore, to use radio-isotopes in this disorder and the range used by Lawrence and colleagues can be seen in Figure 1.

    One of the most comprehensive reviews of poly- cythaemia vera is that of Lawrence, Berlin and Huff (1953). This described the clinical picture in 263 patients of whom 207 were cases of polycythaemia Vera.

    The other cases included those of secondary poly- cythaemia related to anoxia and a further group of patients whom they labelled relative polycythaemia or the polycythaemia of stress, which they accepted showed symptoms similar to Gaisbocks syndrome.

    This review also presented the use of tracer isotopes for the investigation of polycythaemia. Blood vol- umes were measured using red cells labelled with P.

    Studies on red-cell survival and red-cell production were carried out using N labelled glycine and Fe iron. Using a scintillation counter, splenic erythro- poiesis was detected in some cases. From the range of isotopes evaluated for therapy of polycythaemia Vera, radioactive phosphorus P emerged as the isotope of choice.

    The mode of administration of P was to start with a dose of 111 MBq followed by a careful follow- up and phlebotomy if necessary. After IO-12 weeks following re-evaluation, a further dose of 11 l- 118 MBq was given. The mean amount of 12P given in

  • 148 Blood Reviews

    FIG. 19. Permntage muviva in 201 c-of polyoythemis vera treated with Pa hued on 67 deceamd canea plum tbm living rho hew survived at lsvt to the time for whiob the percentage ia calculated. Contact with seven onea hu hem lat, but their dumtiolu me measured only to the date at which they were 1-t knom to be alive. The sutival ia plotted on II probability scale. Sines the point. lie uentially on a atmight line, the longwvitia follow a normal distribution.

    The median survival is abom to bs 13.9 y-.

    Fig. 2 Median survival in polycythaemia Vera. (Reproduced with permission from I), including original caption).

    an initial six-month period averaged 251 MBq. The response of patients was variable. Some patients only appeared to require one course of therapy, a group of 20 patients lasted longer than 5 years without treat- ment and 5 patients 10 years. The results of treat- ments were a virtual relief of symptoms and resolution of physical signs.

    The number of patents treated and the length of follow-up enabled the authors to estimate the median survival of patients with polycythaemia vera treated by 32P as 13.2 years (Fig. 2.) This contrasted with the data of Videbaek (1950), which showed survival time half this value with venesection, phenyl-hydrazine and radiotherapy. Lawrence and colleagues also showed a reduction in thrombotic events; in the studies, there were 144 patients living and 57 dead. Of the dead patients, 15 died of what was called at the time chronic myeloid leukaemia of whom a proportion, difficult to estimate, transformed into acute leukaemia.

    The use of radioactive phosphorus in the treatment of chronic myeloid leukaemia

    Radioactive phosphorus was also used in the treat- ment of chronic myeloid leukaemia (CML). In 1948, Lawrence and co-workers6 reported their experience of treating 129 patients from 1936 to 1947, a period of 11 years.

    Some patients had been previously treated with X-ray therapy, either total body irradiation. fashion- able at the time, or to the spleen. It is interesting to note that 3 patients died of miliary tuberculosis with no previous history. Treatment was often given as 37-74 MBq per week over 4-8 weeks, with care being taken not to induce a cytopenia.

    Because of the mixed nature of the cases, the authors were able to make general comments only but some good clinical results were obtained (Fig. 3). They noted that it was not possible to extend life by irradiation.

    They noted that approximately one-third of patients died of acute leukaemia. At the time of pub- lication, 33 of the 129 patients were alive 5 years after presentation. One patient lived for 11 years controlled successfully by P (Fig. 4.)

    It would appear overall that the results of P injec- tions were very similar to radiotherapy to the spleen and for whole body irradiation.

    Radioactive phosphorus in chronic lymphocytic leukaemia

    From its earliest availability, P was used in the treat- ment of chronic lymphocytic leukaemia (CLL) and 100 patients treated between 1936 and 1948 were reported by Lawrence et al in 1949; 58 of the patients also had localized radiotherapy to local lymph nodes or spleen.

    It is interesting to read that, in contrast to the 3 patients who died of miliary tuberculosis in CML, there was none in patients with CLL. There were 71 males and 29 females and the age difference was between 20 and 60 years with a mean of 53 years.

    The method of treatment was by giving 37- 74 MBq for 48 weeks repeated when the blood count or symptoms warranted it.

    The changes sought with therapy were an improved red-cell count and decrease in lymphadenopathy and splenomegaly. No attempt was made to bring the lym- phocyte count to normal for fear of bone-marrow damage. The response to therapy in this article is shown by examples and indicates how the lymphocyte counts can be controlled over several years (Fig. 5.)

    Survival is shown in Figure 6 and, from this, the authors calculated that the average survival was 4.5 years. An interesting comparison in terms of relation- ship with acute leukaemia to radiation therapy was made between CML and CLL. At least one-third of patients with CML died of a blast cell transformation, whereas only 2 with CLL died with this picture. It was noted that the total amount of j2P given to patients with CLL was lower than with CML. This series established for the first time that haemoglobin level is a very important prognostic feature in CLL (Fig. 7).

  • Radioactive phosphorus in haematology 149

    Fig. S.-RI. R., 57 year old woman. Definite improvement of the white cell count and size of the spleen foilowing administration of a small nnloutlt of P=.

    Fig. 3 Clinical follow-up in a patient with chronic myeloid leukaemia. (Reproduced with permission from 1 including original caption).

    r

    0 I 2 3 4 6 7 6 9 IO II

    0 LIVING, p32

    m LIVING, p32 and X-ray

    DEAD, p32

    DEAD, ~32, and X-ray

    Duration (years)

    Pig. 8.---Chronic myelogenous leukemia with radiation therapy. The p;~tient living eleven years after onset received only Ps2 until this past xcar, when some ~NXI~ roentwl radiation to the spleen has been admin- I~tcrtd. The nvcrnge duration to date is 3.7 years.

    Fig. 4 Survival in chronic myeloid leukaemia. (Reproduced with permission from lo, including original caption)

  • Fig. Z.-By infrequent ntllllillihtr;tti(lll of I: intrnvcnr,uslg, in (loses from 0.5 to 4 millicuries, the I\ liitc rc>ll> lxivc tIcen kcljt llcar nornl;tl it, nunil)er anti the patient, a 41 +cr oltl n1a11 L\ it!] chronic Ivml~li;~tic leu- kcmin, has carried on a normal liie withtOut synilItc0ilh (i,:: shf~n in millicurics, ret1 Mood cells in millions. hcmogl~~l~in in xr;rms :tntl \vhitc I~l~od cells Zild thronil)ocytrs in til0~~s~l~tl~).

    Fig. 5 Clinical follow-up in a patient with chronic lymphocytic leukaemia treated by P. (Reproduced with permission from , including origin al caption).

    Fig. 5.---l

  • Radioactive uhosuhorus in haematoloev 15 1

    Fig. 7 Survival and haemoglobin Ie~el in chronic lymphocytic leukaemia. (Reproduced with permission from -. including original caption).

    Fig. 6.yConlpariso? of. duration of disease !in years) -with percentage of ~~~hog$~m on adnnsslo? 111 95 cases of chronic lymphatic leukemia treated

    . The dotted lines are for average duration of deceased patlents.

    The use of radioactive phosphorus in the treatment of myeloma

    An evaluation of the use of radio-isotopes in the treatment of multiple myeloma (MM) was published by Lawrence and Wasserman in 1950. The alterna- tive treatment at the time was X-ray therapy to local sites of disease, stilbamidine or urethane.

    In all, 24 patients were recorded in detail and the small literature on the subject reviewed. The authors also evaluated radioactive strontium Sr but found that it was too toxic for haemopoietic bone marrow because of its relatively long half-life of 50.5 days. Overall, the results were no better than X-ray therapy or stilbamidine.

    However, in a limited number of cases, the symp- tomatic relief was striking and remissions lasting months were obtained.

    Protein electrophoresis was not available at the time and effects on paraprotein remain unknown. Dosage was 37 MBq once or twice a week for 4-6 weeks.

    Radioactive phosphorus treatment and the development of leukaemia

    The series of Lawrence Berlin and Huff in 1953 was the largest and most significant in the world literature. It represented the long-term follow-up of 207 patients with polycythaemia vera and it was noted that

    15 patients at the time of publication developed what was called chronic myelogenous leukaemia and went on to develop acute leukaemia but the median sur- vival of polycythaemia vera treated with radioactive phosphorus was 13.2 years (Fig. 2). Thus, it would appear that radioactive phosphorus prolongs life in polycythaemia vera but at the risk of leukaemic trans- formation. This contrasted with the work of Chievitz and Theide, (Fig. 8), which illustrates the virtue of myelosuppressive therapy. Thus began a controversy on the use of P in polycythaemia Vera, which may be summarized as follows:

    I. Radiation is leukaemogenic and therefore P should not be used in the treatment of polycythaemia Vera.

    2. Patients with polycythaemia not treated with myelosuppressive therapy may develop leukaemia but treatment with radioactive phosphorus enhances this tendency.

    3. Treatment with P allows the patients to live long enough to develop leukaemia.

    The condition of CML referred to by Lawrence et al in 1953 is in fact a very different condition from the Ph- chromosome-positive leukaemia to which this term is now applied. The patient no longer has a high red-cell count and may become anaemic, the anaemia is leuco- erythroblastic in type, the marrow is hypercellular and shows ineffective erythropoiesis and may evolve to

  • 152 Blood Reviews

    2 4 6 8 IO 12 14 16

    Duration of disease Wears)

    -I+H+H+ Untreated . . . . . . . . . Veaesection alone

    X-ray therapy alone - - - - - - Various combinations with X-ray therapy

    Fig. 8 Survival of patients with polycythaemia vera with different forms of treatment. (Reproduced with permission from ).

    myelofibrosis. There is usually hepatosplenomegaly due to extramedullary haemopoiesis. This syndrome is referred to by many as spent polycythaemia but in 1947 at least 24 synonyms could be found in the literature (Table l).>

    Since the original series of Lawrence et al in 1953,j a large volume of literature has accumulated on the various modes of treatment of polycythaemia vera and their effects on the thrombotic and haematologi- cal sequelae. However, the series of patients published are not strictly comparable because of different diagnostic criteria and treatment. Various alternative modes of therapy have been used; many bizarre and with severe side-effects (Ref.*; Table 2).

    In an attempt to solve this problem, the Poly- cythaemia Vera Study Group (PVSG) was set up in the USA in the 1960s under the leadership of Louis Wasserman.?

    Diagnostic criteria were established and a three- way randomization between phlebotomy, radioactive phosphorus and chlorambucil was instituted.

    After five years of the study, it was appreciated that chlorambucil was leukaemogenic and this arm of the trial was terminated. In his review, Wassermann2 noted that the median survival with phlebotomy was 13.9 years, chlorambucil 9.1 years and 32P 11.8 years. In 1979, the PSVG went on to evaluate hydroxyurea but this therapeutic trial was terminated after 5 years because of lack of funds. However, Tatarsky and Sharon 1997 continued to follow up the patients entered into this trial, added further ones and reviewed the literature.

    They reported 71 patients followed up for a mini- mum of 5 years and noted that acute leukaemia occurred in 4 patients. This is not significantly different

    Table 1 The synonyms of aleukaemic myelosis from Heller, Lewisohn and Palin

    A Leukaemia

    Aleukemic myelosis Aleukemic leukaemia Pseudoleukaemia

    B Anaemia

    Osteosclerotic leukaemia Atypical myelosis Megakaryocytic myelosis

    Leukaemia

    Myeloid splenic anaemia

    Leuko-erythroblastic anaemia Leuko-erythroblastosis Osteosclerotic anaemia

    C Spleen and/or liver

    Splenomegaly with anaemia and myeloma Myelophthisic splenomegaly Aleukemic hepatosplenic myelosis Agnogenic myeloid metaplasia of the spleen Myeloid megakaryocytic hepatosplenomegaly Splenomegaly with sclerosis of the bone marrow Splenomegaly with myeloid transformation Splenomegaly with anaemia Myeloid splenomegaly without myelocytaemia

    D Bone marrow

    Myelofibrosis Myelosclerosis Osteosclerosis

    Table 2 Methods of treatment of polycythaemia vera (after Wasserman)

    Variations on bloodletting General or topical Phlebotomy Scarifying Cupping Leeching Iatrogenic hookworm infestation

    Miscellaneous Gastric lavage (to remove Castles Intrinsic Factor (IF)) Gastrectomy to remove IF (stimulus to bone marrow) Diet (iron-free, high-fat, low-purine) Splenic extracts, liver extracts, splenectomy a interferon Chemical Benz01 and derivatives Phenylhydrazine: acetylphenylhydrazine (aniline derivative) Onions (onion oil: N-propyldisulphide); Arsenic: Fowlers solution (10 drops); Oxygen inhalation (for bone-marrow anoxia) Radiation: Total-body. splenic, long bones, stomach

    Radium, thorium X, Grenzstrahlen Radioactive-phosphorus, sodium, gold, zirconium, yttrium.

    Chemotherapy Nitrogen mustard, busulfan, thiotepa, triethylene melamine, daraprim, alkeran, chlorambucil, cyclophosphamide, procarbazine, pipobroman (Vercyte). azaribine, dibromannitol, hydroxyurea

  • Radioactive phosphorus in haematologv 153

    from the phlebotomy group but the numbers are small. In a review of the literature, however, the inci- dence of acute leukaemia varied from 2% to 10.5%.

    A similar series that followed on from the PSVG trial was reported by Najean et alzi and extended further in 1997. As in other series, the number of patients receiving phlebotomy alone diminished with time as patients were transferred to myelosuppres- sion and patients on IP therapy were given hydroxy- urea as the total dose of IzP given increased. These authors also found that in the phlebotomy arm the incidence of myelofibrosis increased confirming the findings of Nand et al. The authors also found that the introduction of myelosuppressive therapy reduces this tendency.

    It is now highly unlikely that another trial evaluat- ing the use of P in polycythaemia will ever be under- taken. The median survival for patients treated with ?P in polycythaemia was 13.5 years in the series of Najean and Rain6 comparing very well with the find- ings of Lawrence et al in the past. What is most significant, however, is that the life-expectancy of a similar group of people in France is 15.2 years, repre- senting a difference of only 10%. Perhaps the poten- tially harmful effects of myelosuppressive therapy are balanced by regular medical supervision and control of haematocrit and platelet count.

    Although hydroxyurea is probably the recom- mended treatment on the younger patients. the fact that P represents a very effective, complication-free, form of treatment for the elderly with long periods of remission makes it the treatment of choice for patients over the age of 65.

    The use of P in CLL and CML was superseded by alkylating therapy. The results obtained by Lawrences group at the Donner Laboratories with jzP in retro- spect do not seem all that bad in comparison to agents such as chlorambucil and busulphan respectively, though strict comparisons on a historical basis are not possible.

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