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Radioactive phosphorus in the treatment of polycythaemia a review of the years' experience
Clin. RadioL (1967) 18, 287-291 RADIOACTIVE
PHOSPHORUS
A REVIEW
IN THE TREATMENT
OF TEN
OF POLYCYTHAEMIA
YEARS' EXPERIENCE
KEITH ARTHUR
From the Radiotherapy Department, United Birmingham Hospitals One hundred and fifteen patients treated for polycythaemia vera by radioactive phosphorus are studied. The results are compared with those described by Perkins, Israels and Wilkinson (1964) for patients treated by cytotoxic drugs alone. Overall results are found to be very similar, the loss of patients treated by the isotope method through acute leukaemia being balanced by a greater proportion of patients in the non-irradiated group dying of uncontrolled polycythaemia and its complications. A detailed study of irradiated patients with polycythaemia who developed acute leukaemia is undertaken in an attempt to establish any common factors. A two-fold incidence over the expected number of malignant tumours is noted in the series. leucocyte alkaline phosphatase value has been found to be a most useful supplementary finding, but this investigation was not available when the majority of the patients in this series were first seen. For inclusion in this series, a raised red blood count together with 2 or more of the remaining features noted above were considered the minimum criteria. Cases of polycythaemia secondary to other medical conditions, e.g. cardio-pulmonary disease, were excluded. Age and Sex Distribution.--Figure 1 illustrates the age distribution of the cases under consideration. The extremes of age noted are 38 and 80 years while 2 peaks occur; a major peak in 60-64 year group, and a lesser in 50-54 year old group. The MATERIAL mate : female ratio in this series was 2 : 1. This Patients registered in this department as is more in agreement with the findings of Wassercommencing treatment with p~2 between 1950 and man (1954) ( 1 . 8 : 1 ) than Perkins, Israel and 1960 inclusive were studied, allowing for a 'follow- Wilkinson (1.3 : 1) (1964). It was of interest to note that in 4 cases in this up' of 5-15 years. One hundred and twenty four patients were registered during this period, but 9 series, a parent of the patient had suffered from were excluded. Three of these 9 patients were later the same disease while in 1 case both the patient's proved to have secondary polycythaemia (1 father and grand father were sufferers. arterio-venous fistula of lung, 1 nephritis, and 1 History and Presentation.--Attempting to assess cardiac lesion), 3 patients died within 1 month of the length of history in Polycythaemia is most initial registration allowing for no useful study, difficult. Symptoms such as headache and high while in the remaining 3 patients adequate follow- colour are notoriously vague and practically up data on clinical condition, treatment and impossible to define accurately in terms of time. haematological studies were not available for study. The case histories of this series were carefully Criteria.--Haematological findings noted in poly- studied and the most common presenting symptoms cythaemia are a raised red blood corpuscle count and signs noted. The findings are summarised in (>6,000,000 per c.mm.), leucocytosis, thrombo- Table 1. cytosis, raised haemaglobin (> 17.5 g.) and a The predominance of a thrombotic episode in Packed Cell Volume of 55 % or more. Splenomegaly Table 1 underlines the fact that minor symptoms is a common finding. More recently a raised are probably ignored for a considerable period and 287 SIr~cz its introduction in 1940, radioactive phosphorus has been widely used in the treatment of polycythaemia vera. It has been used in the Birmingham Region since 1948 and the object of this survey, while recognising the limitations of a retrospective study, was to assess the usefulness of p32 in terms of efficiency and complications. The well recognised suggestion of increased risk of acute leukaemia when p32 is used in this condition was particularly of interest in view of the recent excellent report of Perkins, Israels and Wilkinson (1964) who found no case of acute leukaemia in a series of 127 patients treated by cytotoxic drugs alone, while offering as good a prognosis as did previous irradiated series.
288
CLINICAL
RADIOLOGY
25-
count was controlled and have had no psychotic relapses for periods of up to 7 years (minimum follow-up four years). Gout was not a common finding in this series (only 2 cases). Tile raised serum uric acid levels found so commonly in the series of Perkins, Israels and Wilkinson (1964) was not studied in this group. Neither was haemorrhage, noted in 1 7 ~ o f their series, a presenting feature of note in this series.
z
35
40
45
50
55 60 AGE (YEARS)
65
70
75
80
FIG. 1 Age distribution of Patients.
it is only a major catastrophe which frequently brings the diagnosis to light. Attention is drawn to the 5 ~ of patients presenting with hyperaesthesia of limbs. All but 1 of these patients complained solely of 'pins and needles' in the limbs, presumably an ischaemic phenomenon due to increased blood viscosity. In 7 ~ of patients, polycythaemia was an incidental finding in a general medical examination. Two of these patients were under investigation for abdominal pain (no splenomegaly in either case), 2 were suffering from rheumatoid arthritis while 3 patients were admitted with a diagnosis of depression. All 3 of this last group showed a prompt return to mental normality when the blood TABLE 1 PRESENTING FEATURES IN ORDER OF FREQUENCY
Presentation Thrombosis (all sites) Dizzint~ss Headache Incidental finding Pruritus (generalized) Breathlessness Splenic pain Hyperaesthesia of limbs High colour Malaise Other
30 7 6 5 5 5 4 4 14
RESPONSE TO RADIOACTIVE PHOSPHORUS In an attempt to assess the efficiency of p32, the cases were studied in detail over the follow-up perigO, gya~i!a,ble and eacIi case' allotted to 1 of the following 3 arbitrary categories :-(i) Good response - - return of blood count to normal and / or complete relief of symptoms, for a minimum of 12 months. (ii) Fair response - - improvement in haematological and/or clinical findings but venesection or further therapy required for full control. (iii) Poor response - - poor haematological and clinical response. Using this classification, the findings were as follows : Good response 63 Fair response 25 Poor response 1 2 ~ 100K In the majority of patients, a fairly consistent cycle was noted, control of clinical and haematological finding being maintained for a similar period of time with each dose of pa2. Such cycles, however, appeared applicable only to the individual patient rather than to the overall series. In the group of good responders an average 22 months was noted between treatments, the range being 14-46 months. In 5 patients, a marked shortening of the cycle was noted in the 3 years preceding death. These patients, possibly unwisely, received extra doses of Pa~ in this period, and 3 developed acute leukaemia terminally. Alternative Methods of Treatment. Nine patients in this series received treatment by chemotherapy at some stage of their management. The numbers and doses used are thought to be too small for study, nor likely to have influenced the overall picture. Complieations of pa~ Therapy.--Intra-venous injection was the route of administration of pa2
RADIOACTIVE
PHOSPHORUS
I N T H E T R E A T M E N T OF P O L Y C Y T H A E M I A
for all but 2 ~ of doses in this study. No local complications at the injection site were noted. Three cases of pyrexia following injection were traced to 'pyrogen' contamination of water used for dilution. Three patients developed splenic pain following treatment, presumably due to a perisplenitis. All 3 patients had gross splenomegaly. The predominant haematological complication following p32 therapy (acute leukaemia is considered separately) was thrombocytopenia. This was noted in 8 patients. In 5 patients, thrombocytopenia was a purely temporary finding, though recurrent in 3 patients following successive doses of p32. In 3 patients persistent thrombocytopenia developed. All 3 of the latter patients had received multiple doses (total 46, 54, and 50 mcs.) over periods of 7, 8 and 10 years and it seems likely that their diminished platelet count was the most marked feature of a low-grade pancytopenia. This is concluded since 2 of the patients developed myelofibrosis and died within 18 months of developing thrombocytopenia, while the 3rd has survived 3 years to date with no further treatment buL a persistent thrombocytopenia and mild anaemia. Two patients experienced haemorrhage as a result of their thrombocytopenia. Four patients developed a temporary anaemia following p32 therapy. All had generous venesections preceding injection. Three patients have developed a persistent anaemia which has proven refractory to Iron, B 12 and folic acid. One of these patients has been shown to be suffering from splenic haemolysis. The remaining 2 cases of anaemia are attributed to bone-marrow fibrosis. Iron Deficiency in Polyeythaemia.--Iron deficiency is of interest in this disease, since one would expect such a deficiency to cause bone-marrow stimulation and hence aggravate the primary condition. Adequate data on iron deficiency was
289
unfortunately only available in 75 cases. In 44 of these patients, colour index and M.C.H.C. values were consistently normal. Fifteen patients showed evidence of iron deficiency solely on those occasions when further p82 therapy was indicated but returned to normal values, without iron therapy, when treated with PZZ. In the remaining 16 cases, a persistent iron deficiency was noted which did not respond to pa~ and, indeed, did not show any fluctuation with the overall haematological picture. Iron therapy was instituted in 6 patients with no apparent response. MORTALITY Forty-two patients in the present series have died to date. Table 2 lists the causes of death under 3 headings. Group I represents patients in whom failure to control their polycythaemia is considered to be a major factor in causing death. Group II ('Marrow' deaths) are those patients dying of acute leukaemia or myelosclerosis. Group III are the remaining group dying of miscellaneous causes. The expected number of deaths in such a group (estimated from Life Table for England and Wales 1951, Registrar General's Decennial Supplement) from time of first treatment is 13.93. Thus the ratio observed mortality. 42 expected mortality is ~ = 3-01. This agrees with the figure of 3 found by Perkins, Israels and Wilkinson (1964) in their non-irradiated series. This figure would appear to be a more accurate indication for comparison than median survival which is extremely difficult to estimate for such a group of patients. MALIGNANCY IN POLYCYTHAEMIA (a) Acute Leukaemia.--From Table 2 it will be noted that 9 patients have died of proven acute leukaemia. Two further patients died at home,
TABLE 2 DEATHS IN POLYCYTHAEMIA
TOTAL---42 Polyeythaemic deaths Cerebral thrombosis Cardiac failure Mesenteric thrombosis Coronary thrombosis Femoral thrombosis with gangrene
Marrow deaths 5 5 1 3 1
15
Acute leukaemia Suspected acute leukaemia Myelosclerosis
Other deaths 9 2 4
15
Biliary peritonitis Pulmonary embolus (cholecystectomy) Carcinoma of colon Carcinoma of rectum Carcinoma of bronchus Chronic nephritis Ruptured appendix Cardiac catheterisation Not known
1 1 2 1 2 1 1 1 2 12
290
CLINICAL
RADIOLOGY
the diagnosis of acute leukaemia having been made developed myelofibrosis. Splenomegaly was noted conclusively on clinical grounds but without in the remaining 54 patients of whom 6 developed positive haematological proof having been proven acute leukaemia, 2 suspected acute obtained. Yet 1 further patient died of acute leukaemia, and 3 myelofibrosis. leukaemia 3 years after a positive diagnosis of It will be noted in Table III that none of the polycythaemia but is excluded since he received no cases developing acute leukaemia was classified active therapy of any sort (cf. Williams and Mendel as a 'good responder' to P~. (b) Malignancy Other than Acute Leukaemia.-1954). The expected incidence of acute leukaemia in No cases of chronic leukaemia have been noted this gronp, based on Birmingham Regional Cancer in this series. Nine patients have developed a malignant tumour Registry figure 1960-62, is 0.02 case. Thus, the noted incidence is at least 500 times the expected to date. In all cases the polycythaemia was proven figure. This finding agrees those of Wiseman et al at least 3 years before the development of the (1951) who found that 12 out of 40 deaths in their tumour, and no specific relationship appears to series were due to acute leukaemia and with the exist between the 2 findings. The tumours noted average figure of 11-12~ cases likely to develop are :--Bronchial carcinoma (3), carcinoma of leukaemia as q u o t e d by Perkins, Israels and colon (2), and 1 each of carcinoma of breast and Wilkinson (1964) when they surveyed the published rectum. The remaining 2 tumours were a rodent data on incidence of acute leukaemia in irradiated ulcer and a malignant abdominal mass which was polycythaemia patients. not biopsied. From Regional Cancer Registry A detailed study was made of the records of figures, the estimated expected number of cases patients developing acute leukaemia in an attempt developing a tumour is 4.24. The incidence is thus to establish any common factors which might be of increased by a factor of 2.1 : 1. significance. As shown in Table 3, however, the DISCUSSION group was remarkable for its variety only. Age and sex ratios were similar to those for the whole The work of Perkins, Israels and Wilkinson series. Length of history, white blood count (1964) has quite conclusively shown that polythroughout treatment and other forms of treat- cythaemia may be very adequately treated without ment showed no consistent patterns. Total dose of the use of irradiation. Their survey of published p3~ varies from 12 mcs. to 60 mcs. (and one excluded data on the incidence of acute leukaemia in previous case had no treatment). irradiated series shows an average figure of 11 ~ . When splenomegaly was studied, an interesting The objects of the present study therefore is to fact emerged, though the statistical significance of survey the efficiency and complication rate in this such small numbers is dubious. Adequate data on region in order to decide whether or not p3~ splenic size throughout the patients' history was should continue to be the premier treatment of available in 96 cases. In 42 patients, splenomegaly polycythaemia. was not noted at any stage. Three patients in this Out of the present series of 115 cases, 9 have group developed acute leukaemia while one more died of acute leukaemia and 2 have almost certainly TABLE 3 ACUTE LEUKAEMIA COMPARATIVE FACTORS
No.
1st s y m p t o m to l e u k a e m i a yrs. 2 m. 12 13 5 5 6
yrs. yrs. yrs. yrs. yrs.
0 m. 2 m. 0 m. 6m. 3 m.
14 yrs. 0 m. 8 yrs. 5 m. 4 yrs. 6 m .
1st pz2 to leukaemia 8 yrs. 0 m. 12 12 4 5 5
yrs. yrs. yrs. yrs. yrs.
0 m. 11 m. 1 m. 0 m. 11 m .
3 yrs. 0 m . 8 yrs. 1 m. 3 yrs. 9 m .
Response to p32
Splenomegaly
Fair
Persistant
Poor Fair Poor Poor Fair
Persistant Temporary None Temporary None
Poor Poor Poor
Persistant Temporary None
Other therapy D X R 400 r. Venesection Venesection Daraprim Venesection Venesection D X R 800 r. T.E.M. Venesection Venesection Venesection
Total dose P ~
WBC througho~ treatment
60 54 59 13 20
mcs. mcs. mcs. mcs. mcs.
< 10,000 > 15,000 10-15,000 < 10,000 < 10,0i000
43 12 50 22
mcs. mcs. mcs. mcs.
> 15,000 < 10,000 10-15,000 < 10,000
R A D I O A C T I V E P H O S P H O R U S IN THE TREATMENT OF P O L Y C Y T H A E M I A
suffered the same fate. These figures fall in line with those published in previous irradiated series. Since Perkins, Israels and Wilkinson did not have a single case of acute leukaemia in their very similar (127) group, and since acute leukaemia is the typical radiation-induced leukaemia, the only possible inference is that P~ is the precipitating factor m this complication. It will be recalled, however, that 1 patient, excluded from this series, died of acute leukaemia without ever receiving any active therapy. A detailed study of those cases dying of acute leukaemia failed to exhibit any common factors of dosage, age, etc. It would seem possible that in a proportion of patients, the bone marrow may be in such an abnormal state that PaZ over a period of time gives rise to a frank malignant change. The work of McDiarmid (1965) and others on chromosomal change following pa2 therapy may give an insight into such changes. The overall results in this series, however, bear a close similarity to the findings of Perkins, Israels and Wilkinson, whose figures in turn were similar to previous irradiated series of Lawrence (1955). Thus 42 out of 115 patients in the present study have died as compared with 44 out of 127 in the non-irradiated series. The ratio of observed mortality : expected mortality is 3 for both series. This similarity occurs because the increased death rate due to acute leukaemia in the irradiated patients is balanced by the larger proportion of patients in the non-irradiated series who die of complications of polycythaemia (469/00 of deaths). It would appear, in fact, that pa~ gives a superior degree of control of the disease at the expense of an increased risk of malignant change in the bone marrow. It is also a more simple mode of treatment, and more economical in terms of patient and doctor time. It may be possible, by limiting the number of doses of pa~ and supplementing, as required, with cytotoxic drugs, to further improve the prognosis of polycythaemia by minimising the failings of the present forms of treatment. The two-fold increase over the expected incidence of malignant tumours (9:4.24), excluding acute leukaemia, is a disquieting finding. No conclusion can be drawn as to any cause and effect relationship i.e. with regard to p3z, from a single paper, but it would be of interest to know if such an increase has been noted in other series. CONCLUSIONS The results of this series fall into line with those of previous published data on patients treated with radioactive phosphorus for polycythaemia
291
vera. Perkins, Israels and Wilkinson were able to show similar figures in their study of patients treated with cytotoxic drugs but no isotopes. It must therefore be established that, if one studies the overall series' results, either method of treatment gives satisfactory control of the disease. Radioactive phosphorous is undoubtedly a simpler and more convenient form of treatment, being far less time-consuming in terms of patient and doctors' time. However, 10 to 12 per cent of patients treated by this isotope will eventually die of acute leukaemia, a risk not found in the nonirradiated patients described by Perkins, Israels and Wilkinson. It is suggested however, that a more efficient control of the disease may be obtained with radioactive phosphorus than with cytotoxic drugs. It is further suggested that, by a more discriminate use of p32 and in particular the avoidance of repeated dosage in patients who fail to exhibit an adequate response to the isotope, the overall results may be further improved by reducing the number of patients developing acute leukaemia. Where control of the patients' polycythaemia by p~z alone is inadequate, treatment may be supplemented by the use of cytotoxic drugs. In cases of patients with gross splenomegaly, the results of this series suggest that radio-phosphorus should not be employed since the figures hint that these patients may carry a greater risk of acute leukaemia. It is hoped that such a treatment regime may combine the better aspects of isotope and cytotoxic treatment techniques with maximum benefit to the patients. A two-fold increase in malignant turnouts occurring in patients in this series over the calculated expected figure is a disquieting finding. Acknowledgements. The patients studied in this paper were reated by the Consultant Staff of the Radiotherapy Department of the United Birmingham Hospitals. I wish to express my gratitude for permission to study their patients and much helpful advice and encouragement in the study. Dr. J. A. H. Waterhouse and Miss J. Powell of the Birmingham Regional Cancer Registry gave invaluable assistance on the statistical aspects of the paper, and my thanks are due to Miss J. M. Levi and Miss M. Savage of the Regional Cancer FollowUp Department for tracing so efficiently the required case notes. REFERENCES LAWRENCE, J. H. (1955). Polycythaemia--Physiology, Diagnosis and Treatment. N.Y. Mod. Med. Monographs. McDIARNaD, W. D. (1965). Quart J. Med., 34, 133. PERKINS, J., ISRAELS, M. C. G., & WILKINSON, J. F. (1964). Quart. J. Med., 132, 499. WASSERMAN,L. R. (1954). Bull. N.Y. Acad. Med., 30, 343. WASSERMAN,L. R. (1955). Blood., 10, 656. WILLIAMS, M. J. & MENDEL, J. L. (1954). Blood, 9, 189. WISEMAN, B. K., ROHN, R. J., & BARUNCLE, B. H., & MYERS, W. G. (1951). Ann. intern. Med., 34, 311.
PHOSPHORUS
A REVIEW
IN THE TREATMENT
OF TEN
OF POLYCYTHAEMIA
YEARS' EXPERIENCE
KEITH ARTHUR
From the Radiotherapy Department, United Birmingham Hospitals One hundred and fifteen patients treated for polycythaemia vera by radioactive phosphorus are studied. The results are compared with those described by Perkins, Israels and Wilkinson (1964) for patients treated by cytotoxic drugs alone. Overall results are found to be very similar, the loss of patients treated by the isotope method through acute leukaemia being balanced by a greater proportion of patients in the non-irradiated group dying of uncontrolled polycythaemia and its complications. A detailed study of irradiated patients with polycythaemia who developed acute leukaemia is undertaken in an attempt to establish any common factors. A two-fold incidence over the expected number of malignant tumours is noted in the series. leucocyte alkaline phosphatase value has been found to be a most useful supplementary finding, but this investigation was not available when the majority of the patients in this series were first seen. For inclusion in this series, a raised red blood count together with 2 or more of the remaining features noted above were considered the minimum criteria. Cases of polycythaemia secondary to other medical conditions, e.g. cardio-pulmonary disease, were excluded. Age and Sex Distribution.--Figure 1 illustrates the age distribution of the cases under consideration. The extremes of age noted are 38 and 80 years while 2 peaks occur; a major peak in 60-64 year group, and a lesser in 50-54 year old group. The MATERIAL mate : female ratio in this series was 2 : 1. This Patients registered in this department as is more in agreement with the findings of Wassercommencing treatment with p~2 between 1950 and man (1954) ( 1 . 8 : 1 ) than Perkins, Israel and 1960 inclusive were studied, allowing for a 'follow- Wilkinson (1.3 : 1) (1964). It was of interest to note that in 4 cases in this up' of 5-15 years. One hundred and twenty four patients were registered during this period, but 9 series, a parent of the patient had suffered from were excluded. Three of these 9 patients were later the same disease while in 1 case both the patient's proved to have secondary polycythaemia (1 father and grand father were sufferers. arterio-venous fistula of lung, 1 nephritis, and 1 History and Presentation.--Attempting to assess cardiac lesion), 3 patients died within 1 month of the length of history in Polycythaemia is most initial registration allowing for no useful study, difficult. Symptoms such as headache and high while in the remaining 3 patients adequate follow- colour are notoriously vague and practically up data on clinical condition, treatment and impossible to define accurately in terms of time. haematological studies were not available for study. The case histories of this series were carefully Criteria.--Haematological findings noted in poly- studied and the most common presenting symptoms cythaemia are a raised red blood corpuscle count and signs noted. The findings are summarised in (>6,000,000 per c.mm.), leucocytosis, thrombo- Table 1. cytosis, raised haemaglobin (> 17.5 g.) and a The predominance of a thrombotic episode in Packed Cell Volume of 55 % or more. Splenomegaly Table 1 underlines the fact that minor symptoms is a common finding. More recently a raised are probably ignored for a considerable period and 287 SIr~cz its introduction in 1940, radioactive phosphorus has been widely used in the treatment of polycythaemia vera. It has been used in the Birmingham Region since 1948 and the object of this survey, while recognising the limitations of a retrospective study, was to assess the usefulness of p32 in terms of efficiency and complications. The well recognised suggestion of increased risk of acute leukaemia when p32 is used in this condition was particularly of interest in view of the recent excellent report of Perkins, Israels and Wilkinson (1964) who found no case of acute leukaemia in a series of 127 patients treated by cytotoxic drugs alone, while offering as good a prognosis as did previous irradiated series.
288
CLINICAL
RADIOLOGY
25-
count was controlled and have had no psychotic relapses for periods of up to 7 years (minimum follow-up four years). Gout was not a common finding in this series (only 2 cases). Tile raised serum uric acid levels found so commonly in the series of Perkins, Israels and Wilkinson (1964) was not studied in this group. Neither was haemorrhage, noted in 1 7 ~ o f their series, a presenting feature of note in this series.
z
35
40
45
50
55 60 AGE (YEARS)
65
70
75
80
FIG. 1 Age distribution of Patients.
it is only a major catastrophe which frequently brings the diagnosis to light. Attention is drawn to the 5 ~ of patients presenting with hyperaesthesia of limbs. All but 1 of these patients complained solely of 'pins and needles' in the limbs, presumably an ischaemic phenomenon due to increased blood viscosity. In 7 ~ of patients, polycythaemia was an incidental finding in a general medical examination. Two of these patients were under investigation for abdominal pain (no splenomegaly in either case), 2 were suffering from rheumatoid arthritis while 3 patients were admitted with a diagnosis of depression. All 3 of this last group showed a prompt return to mental normality when the blood TABLE 1 PRESENTING FEATURES IN ORDER OF FREQUENCY
Presentation Thrombosis (all sites) Dizzint~ss Headache Incidental finding Pruritus (generalized) Breathlessness Splenic pain Hyperaesthesia of limbs High colour Malaise Other
30 7 6 5 5 5 4 4 14
RESPONSE TO RADIOACTIVE PHOSPHORUS In an attempt to assess the efficiency of p32, the cases were studied in detail over the follow-up perigO, gya~i!a,ble and eacIi case' allotted to 1 of the following 3 arbitrary categories :-(i) Good response - - return of blood count to normal and / or complete relief of symptoms, for a minimum of 12 months. (ii) Fair response - - improvement in haematological and/or clinical findings but venesection or further therapy required for full control. (iii) Poor response - - poor haematological and clinical response. Using this classification, the findings were as follows : Good response 63 Fair response 25 Poor response 1 2 ~ 100K In the majority of patients, a fairly consistent cycle was noted, control of clinical and haematological finding being maintained for a similar period of time with each dose of pa2. Such cycles, however, appeared applicable only to the individual patient rather than to the overall series. In the group of good responders an average 22 months was noted between treatments, the range being 14-46 months. In 5 patients, a marked shortening of the cycle was noted in the 3 years preceding death. These patients, possibly unwisely, received extra doses of Pa~ in this period, and 3 developed acute leukaemia terminally. Alternative Methods of Treatment. Nine patients in this series received treatment by chemotherapy at some stage of their management. The numbers and doses used are thought to be too small for study, nor likely to have influenced the overall picture. Complieations of pa~ Therapy.--Intra-venous injection was the route of administration of pa2
RADIOACTIVE
PHOSPHORUS
I N T H E T R E A T M E N T OF P O L Y C Y T H A E M I A
for all but 2 ~ of doses in this study. No local complications at the injection site were noted. Three cases of pyrexia following injection were traced to 'pyrogen' contamination of water used for dilution. Three patients developed splenic pain following treatment, presumably due to a perisplenitis. All 3 patients had gross splenomegaly. The predominant haematological complication following p32 therapy (acute leukaemia is considered separately) was thrombocytopenia. This was noted in 8 patients. In 5 patients, thrombocytopenia was a purely temporary finding, though recurrent in 3 patients following successive doses of p32. In 3 patients persistent thrombocytopenia developed. All 3 of the latter patients had received multiple doses (total 46, 54, and 50 mcs.) over periods of 7, 8 and 10 years and it seems likely that their diminished platelet count was the most marked feature of a low-grade pancytopenia. This is concluded since 2 of the patients developed myelofibrosis and died within 18 months of developing thrombocytopenia, while the 3rd has survived 3 years to date with no further treatment buL a persistent thrombocytopenia and mild anaemia. Two patients experienced haemorrhage as a result of their thrombocytopenia. Four patients developed a temporary anaemia following p32 therapy. All had generous venesections preceding injection. Three patients have developed a persistent anaemia which has proven refractory to Iron, B 12 and folic acid. One of these patients has been shown to be suffering from splenic haemolysis. The remaining 2 cases of anaemia are attributed to bone-marrow fibrosis. Iron Deficiency in Polyeythaemia.--Iron deficiency is of interest in this disease, since one would expect such a deficiency to cause bone-marrow stimulation and hence aggravate the primary condition. Adequate data on iron deficiency was
289
unfortunately only available in 75 cases. In 44 of these patients, colour index and M.C.H.C. values were consistently normal. Fifteen patients showed evidence of iron deficiency solely on those occasions when further p82 therapy was indicated but returned to normal values, without iron therapy, when treated with PZZ. In the remaining 16 cases, a persistent iron deficiency was noted which did not respond to pa~ and, indeed, did not show any fluctuation with the overall haematological picture. Iron therapy was instituted in 6 patients with no apparent response. MORTALITY Forty-two patients in the present series have died to date. Table 2 lists the causes of death under 3 headings. Group I represents patients in whom failure to control their polycythaemia is considered to be a major factor in causing death. Group II ('Marrow' deaths) are those patients dying of acute leukaemia or myelosclerosis. Group III are the remaining group dying of miscellaneous causes. The expected number of deaths in such a group (estimated from Life Table for England and Wales 1951, Registrar General's Decennial Supplement) from time of first treatment is 13.93. Thus the ratio observed mortality. 42 expected mortality is ~ = 3-01. This agrees with the figure of 3 found by Perkins, Israels and Wilkinson (1964) in their non-irradiated series. This figure would appear to be a more accurate indication for comparison than median survival which is extremely difficult to estimate for such a group of patients. MALIGNANCY IN POLYCYTHAEMIA (a) Acute Leukaemia.--From Table 2 it will be noted that 9 patients have died of proven acute leukaemia. Two further patients died at home,
TABLE 2 DEATHS IN POLYCYTHAEMIA
TOTAL---42 Polyeythaemic deaths Cerebral thrombosis Cardiac failure Mesenteric thrombosis Coronary thrombosis Femoral thrombosis with gangrene
Marrow deaths 5 5 1 3 1
15
Acute leukaemia Suspected acute leukaemia Myelosclerosis
Other deaths 9 2 4
15
Biliary peritonitis Pulmonary embolus (cholecystectomy) Carcinoma of colon Carcinoma of rectum Carcinoma of bronchus Chronic nephritis Ruptured appendix Cardiac catheterisation Not known
1 1 2 1 2 1 1 1 2 12
290
CLINICAL
RADIOLOGY
the diagnosis of acute leukaemia having been made developed myelofibrosis. Splenomegaly was noted conclusively on clinical grounds but without in the remaining 54 patients of whom 6 developed positive haematological proof having been proven acute leukaemia, 2 suspected acute obtained. Yet 1 further patient died of acute leukaemia, and 3 myelofibrosis. leukaemia 3 years after a positive diagnosis of It will be noted in Table III that none of the polycythaemia but is excluded since he received no cases developing acute leukaemia was classified active therapy of any sort (cf. Williams and Mendel as a 'good responder' to P~. (b) Malignancy Other than Acute Leukaemia.-1954). The expected incidence of acute leukaemia in No cases of chronic leukaemia have been noted this gronp, based on Birmingham Regional Cancer in this series. Nine patients have developed a malignant tumour Registry figure 1960-62, is 0.02 case. Thus, the noted incidence is at least 500 times the expected to date. In all cases the polycythaemia was proven figure. This finding agrees those of Wiseman et al at least 3 years before the development of the (1951) who found that 12 out of 40 deaths in their tumour, and no specific relationship appears to series were due to acute leukaemia and with the exist between the 2 findings. The tumours noted average figure of 11-12~ cases likely to develop are :--Bronchial carcinoma (3), carcinoma of leukaemia as q u o t e d by Perkins, Israels and colon (2), and 1 each of carcinoma of breast and Wilkinson (1964) when they surveyed the published rectum. The remaining 2 tumours were a rodent data on incidence of acute leukaemia in irradiated ulcer and a malignant abdominal mass which was polycythaemia patients. not biopsied. From Regional Cancer Registry A detailed study was made of the records of figures, the estimated expected number of cases patients developing acute leukaemia in an attempt developing a tumour is 4.24. The incidence is thus to establish any common factors which might be of increased by a factor of 2.1 : 1. significance. As shown in Table 3, however, the DISCUSSION group was remarkable for its variety only. Age and sex ratios were similar to those for the whole The work of Perkins, Israels and Wilkinson series. Length of history, white blood count (1964) has quite conclusively shown that polythroughout treatment and other forms of treat- cythaemia may be very adequately treated without ment showed no consistent patterns. Total dose of the use of irradiation. Their survey of published p3~ varies from 12 mcs. to 60 mcs. (and one excluded data on the incidence of acute leukaemia in previous case had no treatment). irradiated series shows an average figure of 11 ~ . When splenomegaly was studied, an interesting The objects of the present study therefore is to fact emerged, though the statistical significance of survey the efficiency and complication rate in this such small numbers is dubious. Adequate data on region in order to decide whether or not p3~ splenic size throughout the patients' history was should continue to be the premier treatment of available in 96 cases. In 42 patients, splenomegaly polycythaemia. was not noted at any stage. Three patients in this Out of the present series of 115 cases, 9 have group developed acute leukaemia while one more died of acute leukaemia and 2 have almost certainly TABLE 3 ACUTE LEUKAEMIA COMPARATIVE FACTORS
No.
1st s y m p t o m to l e u k a e m i a yrs. 2 m. 12 13 5 5 6
yrs. yrs. yrs. yrs. yrs.
0 m. 2 m. 0 m. 6m. 3 m.
14 yrs. 0 m. 8 yrs. 5 m. 4 yrs. 6 m .
1st pz2 to leukaemia 8 yrs. 0 m. 12 12 4 5 5
yrs. yrs. yrs. yrs. yrs.
0 m. 11 m. 1 m. 0 m. 11 m .
3 yrs. 0 m . 8 yrs. 1 m. 3 yrs. 9 m .
Response to p32
Splenomegaly
Fair
Persistant
Poor Fair Poor Poor Fair
Persistant Temporary None Temporary None
Poor Poor Poor
Persistant Temporary None
Other therapy D X R 400 r. Venesection Venesection Daraprim Venesection Venesection D X R 800 r. T.E.M. Venesection Venesection Venesection
Total dose P ~
WBC througho~ treatment
60 54 59 13 20
mcs. mcs. mcs. mcs. mcs.
< 10,000 > 15,000 10-15,000 < 10,000 < 10,0i000
43 12 50 22
mcs. mcs. mcs. mcs.
> 15,000 < 10,000 10-15,000 < 10,000
R A D I O A C T I V E P H O S P H O R U S IN THE TREATMENT OF P O L Y C Y T H A E M I A
suffered the same fate. These figures fall in line with those published in previous irradiated series. Since Perkins, Israels and Wilkinson did not have a single case of acute leukaemia in their very similar (127) group, and since acute leukaemia is the typical radiation-induced leukaemia, the only possible inference is that P~ is the precipitating factor m this complication. It will be recalled, however, that 1 patient, excluded from this series, died of acute leukaemia without ever receiving any active therapy. A detailed study of those cases dying of acute leukaemia failed to exhibit any common factors of dosage, age, etc. It would seem possible that in a proportion of patients, the bone marrow may be in such an abnormal state that PaZ over a period of time gives rise to a frank malignant change. The work of McDiarmid (1965) and others on chromosomal change following pa2 therapy may give an insight into such changes. The overall results in this series, however, bear a close similarity to the findings of Perkins, Israels and Wilkinson, whose figures in turn were similar to previous irradiated series of Lawrence (1955). Thus 42 out of 115 patients in the present study have died as compared with 44 out of 127 in the non-irradiated series. The ratio of observed mortality : expected mortality is 3 for both series. This similarity occurs because the increased death rate due to acute leukaemia in the irradiated patients is balanced by the larger proportion of patients in the non-irradiated series who die of complications of polycythaemia (469/00 of deaths). It would appear, in fact, that pa~ gives a superior degree of control of the disease at the expense of an increased risk of malignant change in the bone marrow. It is also a more simple mode of treatment, and more economical in terms of patient and doctor time. It may be possible, by limiting the number of doses of pa~ and supplementing, as required, with cytotoxic drugs, to further improve the prognosis of polycythaemia by minimising the failings of the present forms of treatment. The two-fold increase over the expected incidence of malignant tumours (9:4.24), excluding acute leukaemia, is a disquieting finding. No conclusion can be drawn as to any cause and effect relationship i.e. with regard to p3z, from a single paper, but it would be of interest to know if such an increase has been noted in other series. CONCLUSIONS The results of this series fall into line with those of previous published data on patients treated with radioactive phosphorus for polycythaemia
291
vera. Perkins, Israels and Wilkinson were able to show similar figures in their study of patients treated with cytotoxic drugs but no isotopes. It must therefore be established that, if one studies the overall series' results, either method of treatment gives satisfactory control of the disease. Radioactive phosphorous is undoubtedly a simpler and more convenient form of treatment, being far less time-consuming in terms of patient and doctors' time. However, 10 to 12 per cent of patients treated by this isotope will eventually die of acute leukaemia, a risk not found in the nonirradiated patients described by Perkins, Israels and Wilkinson. It is suggested however, that a more efficient control of the disease may be obtained with radioactive phosphorus than with cytotoxic drugs. It is further suggested that, by a more discriminate use of p32 and in particular the avoidance of repeated dosage in patients who fail to exhibit an adequate response to the isotope, the overall results may be further improved by reducing the number of patients developing acute leukaemia. Where control of the patients' polycythaemia by p~z alone is inadequate, treatment may be supplemented by the use of cytotoxic drugs. In cases of patients with gross splenomegaly, the results of this series suggest that radio-phosphorus should not be employed since the figures hint that these patients may carry a greater risk of acute leukaemia. It is hoped that such a treatment regime may combine the better aspects of isotope and cytotoxic treatment techniques with maximum benefit to the patients. A two-fold increase in malignant turnouts occurring in patients in this series over the calculated expected figure is a disquieting finding. Acknowledgements. The patients studied in this paper were reated by the Consultant Staff of the Radiotherapy Department of the United Birmingham Hospitals. I wish to express my gratitude for permission to study their patients and much helpful advice and encouragement in the study. Dr. J. A. H. Waterhouse and Miss J. Powell of the Birmingham Regional Cancer Registry gave invaluable assistance on the statistical aspects of the paper, and my thanks are due to Miss J. M. Levi and Miss M. Savage of the Regional Cancer FollowUp Department for tracing so efficiently the required case notes. REFERENCES LAWRENCE, J. H. (1955). Polycythaemia--Physiology, Diagnosis and Treatment. N.Y. Mod. Med. Monographs. McDIARNaD, W. D. (1965). Quart J. Med., 34, 133. PERKINS, J., ISRAELS, M. C. G., & WILKINSON, J. F. (1964). Quart. J. Med., 132, 499. WASSERMAN,L. R. (1954). Bull. N.Y. Acad. Med., 30, 343. WASSERMAN,L. R. (1955). Blood., 10, 656. WILLIAMS, M. J. & MENDEL, J. L. (1954). Blood, 9, 189. WISEMAN, B. K., ROHN, R. J., & BARUNCLE, B. H., & MYERS, W. G. (1951). Ann. intern. Med., 34, 311.