Prediction of the dose of radioactive phosphorus in the treatment of polycythaemia vera

Clin. Radiol. (1966) 17, 295-298

PREDICTION OF THE DOSE OF RADIOACTIVE THE TREATMENT OF POLYCYTHAEMIA

PHOSPHORUS VERA

IN

R. H U M E , MARY A. C. COWELL and A. G O L D B E R G From the Department of Medicine, Southern General Hospital; the Regional Radiotherapy Centre, Western Infirmary; and the University Department of Medicine, Western Infirmary, Glasgow

Red cell volume (R.C.V.) measurements have been carried out before and 3-4 months after a single therapeutic dose of radio-active phosphorus (a ~P) in 18 patients with polycythaemia vera. It was found that the absolute fall in R.C.V. correlated with the dose of a2p. (P < 0"01). Because the R.C.V. is directly related to lean body mass (L.B.M.) the statistical significance of L.B.M. to 32p dose requirement was also assessed but was found not to be significant. From the correlation of isotope dose and absolute fall in R.C.V. a scale was constructed for the prediction of 32p dosage in other patients on the basis of an absolute increased level in R.C.V. This scale proved to be useful, and it was found to be more accurate than the total weight method when predicting the dose of isotope. The technique reduced the total dose of z2p administered over 6 and 18 month periods as compared to the figures published by Lawrence (1955), using a titration method of 32p administration, which is important because of the association of terminal acute leukaemia and previous radiation therapy.

EVIDENCE is accumulating that there is an increased incidence of acute leukaemia in patients with polycythaemia vera who have been treated by radiotherapy, including radioactive phosphorus (a2p) (Modan & Lilienfeld, 1964; Perkins et al., 1964). Modan & Lilienfeld (1964) also suggested that this increased incidence was related to the total dose of z2p previously given. Radiophosphorus has proved so effective and convenient in the treatment of polycythaemia vera that it is important to consider any means of diminishing this hazard, short of discontinuation of its use, in particular a method which might reduce total dosage. Since its introduction (Lawrence, 1940) many methods of dose prediction and administration have been tried. Perhaps the most widely used technique has been that of titration, that is, to observe the initial response to a small dose of z2p given intravenously, and repeating the dose at a variable interval of time (Reinhard et al., 1946; Lawrence, 1955; Witts, 1956). A large single injection had been used by Abbatt et al. (1954) and Harman et al. (1955). Verel (1958) considered that the single dose of 32p reduced the exposure time of the bone marrow to the B-rays emitted by the isotope. He suggested that the required single dose is related to the percentage increase of red cell volume (R.C.V.) above normal, and found that most patients would

respond to 5 m.c. z2p when the R.C.V. was about 150 per cent of normal and 7 m.c. 32p when about 200 per cent of normal. We considered it likely that the dose requirement of 32p was directly related to the absolute increase of active marrow and thus to the absolute increase in R.C.V. There is a wide variation in the normal R.C.V. and a relative increase above normal will not accurately reflect the absolute increase in R.C.V. We have therefore correlated the dose of a2p with the absolute fall in R.C.V. in a group of patients and from this have constructed a scale, which enabled us to predict for other patients doses of ~ P on the basis of an absolute increase of R.C.V. above normal. For this purpose it is important to assess with some accuracy the normal R.C.V. in each patient as well as his actual R.C.V. Verel (1958) initially assumed a normal value of 30 ml. red cells per Kg. of body weight, although he later predicted this value on the basis of height, weight, fat thickness and girth. The normal R.C.V. is closely related to lean body mass (L.B.M.) (Muldowney, 1957) and can also be easily calculated from the heighO-body weight formula of Nadler et al. (1962) and Hume & Goldberg (1964). We have used this method of calculation of normal R.C.V. throughout the present study and have also assessed the statistical significance of L.B.M. to 32p dose requirement. 295

296

CLINICAL

MATERIALS A N D METHODS Studies were carried out on 18 patients with polycythaemia vera, diagnosed on criteria previously described by Hume & Goldberg (1964). Blood Volume Measurements: The R.C.V. was measured by the radio-chromium QICr) method in the first 9 patients and derived from the measurement of the plasma volume using radio-iodinated human serum albumin (13~ I.H.S.A.) in the remaining 9 patients. Estimations of the R.C.V. were repeated 3 to 4 months after the injection of z2p. The predicted normal R.C.V. for each patient was calculated by the method of Hume & Goldberg (1964) which is based on the prediction of the total blood volume from height and weight (Nadler, 1962). Measurement of Lean Body Mass (L.B.M.): Lean body mass was calculated from the patient's height and weight according to the formula of Hume and Robb (1965). F o r m u l a : MenL.B.M. = 0.3281 W -1- 0.8618 H - - 29.5336 Women-L.B.M. = 0-29569 W + 1.062065 H - - 43-2933 L.B.M. (Kg.) W = weight (Kg.) H = height (inches) Dosage ofRadiophosphorus: The first 8 patients had been given 32p on the basis of 0.1 m.c. per Kg. of total body weight with a maximum dose of 7.4 m.c. The reduction in R.C.V. at 3-4 months following the injection was plotted against the dose of z2p administered and the linear regression of reduction in R.C.V. on dose of asp was drawn (Fig. 1). All subsequent doses of 32p were calculated from this line in order to reduce the R.C.V. to the predicted normal level. In these 8 patients the largest doses of ~ P prescribed were 7-1 and 7.4 m.c. and these produced a return of the R.C.V. to normal, although extrapolation of the prediction line suggested doses of 10.3 and 9.0 respectively. We have, therefore,

S

00

•

6

5 4

4

g~ 2

I

~

FIG. I FIG. ] ~ T h e

2 3 I D R O P IN R.C.V.Oitres)

2

3

FIG. 2

linear regression of reduction of R . C . V . o n

dose o f a~p for the first 8 patients is drawn. FIo. 2 - - T h e

linear regression o f reduction o f R.C.V. o n dose o f a~p f o r the 18 patients is d r a w n .

RADIOLOGY

accepted 7.5 m.c. a2p as the maximum dose pres. cribable for any patient irrespective of the magni. tude of the increased R.C.V. RESULTS Relationship of Dose of 32p to Reduction in R.C.V. and L.B.M. The means and standard deviations of X~ (Drop in R.C.V.), X2 (Dose of z2p) and X8 (L.B.M.) for the 18 patients are shown in Table 1. There was a TABLE 1 THE MEANS AND STANDARD DEVIATIONSOF X 1 (DROP IN R.C.V.), X 2 (DOSE OF 8sp) a n d X 8 (L.B.M.) EOR THE 18 PATIENTS ARE SHOWN. THE CORRELATION COEFFICIENTS rls BETWEEN X 1 AND Ks, r13 BETWEEN X 1 AND X 3 AND rs3 BETWEEN K s AND X 3 ARE ALSO EXPRESSED

Mean Standard Deviation Correlation Coefficient

D r o p in R.C.V.

D o s e o f a2p

L.B.M.

1540-4

5 '6

47.4

842.4

1.1

3.0

rla = 0.35

rsz = 0.55

rls =

+ 0.69

significant correlation between X1 and X2 (r12= 0-69) and between X~ and X~ (r2z = 0.55) but not between X 1 and Xz (rla =0.35). The linear regression of Xx on X~ and X~ is given by the equation X1 = 552.15 X2 - - 4.2330 X z - - 1350.9 Since the coefficient of X3 is not significantly different from zero, Xz (L.B.M.) can be ignored and the linear regression of X1 on Xz becomes Xi = 532.03 X2 - - 1438.9 The standard deviation of deviations of X~ from this regression line is Sd = 626.1. The ratio of Sd to the mean of the Xl's = 626.1/1540.4 = 0.406 = 40.6~. Comparison Between the First 8 Patients and Remaining 10 Patients with Respect to Effectiveness of Dose Prediction The dose of 32p administered to the first 8 patients was predicted on the basis of 0.1 m.c. 32p per Kg. total body weight with an upper limit, irrespective of weight, of 7.5 m.c. The dose of ~2p given on 14 occasions to the next ten patients, 4 having repeated doses, was calculated from the line (Fig. 1) which related the dose of 32p to the drop in R.C.V. occurring in the first 8 patients. Assuming a change from the normal RIC.V. of plus or minus 200 ml. of red cells as an acceptable error, it can be seen that

RADIOACTIVE

PHOSPHORUS

PREDICTED from WEIGHT

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

PREDICTED from GRAPH

1200 I000 8oo o

600

400

0

200

*o 200

•

-."

I. g

.....

_o_ _o_ _

400 500 8OO

FIG. 3 "Predicted from Weight" column shows the effect of a single dose of 82p, predicted on the basis of the patient's weight, in the first 8 patients and the deviation from the patient's normal R.C.V. of the final R.C.V. "Predicted from Graph" column shows the effect of a single dose of z~P predicted from the graph (Fig. 1) in the next 10 patients. The results obtained by the "prediction from graph" are significantly better than those obtained by the "prediction from weight" (P< 0.05).

there is a significant improvement in the response when the prediction line is used (Fig. 3). (X ~ = 4.03; p < 0.05). DISCUSSION Analysis of the results shows that the reduction in red cell volume following the administration of 3~p is directly related to the dose of ~2p given. (r = 0.69; P <0-01). However, the standard deviation of deviations from the regression line of X 1 (drop in R.C.V.) and X2 (dose of ~2p) is large (1540 _+ 626). This variation in response is due mainly to partial responsiveness in 2 patients (Fig. 3). Thirty-one patient doses have now been prescribed from the prediction graph in Figure 2 and only one patient developed a mild anaemia. (Hb. 10.8 G ~ . P.C.V. 36~). Second doses in 5 patients did not show any alteration in the dose response pattern. There have been 27 complete remissions and 2 inadequate responses and 2 complete failures. Using this single dose prediction technique the average dose of 32p per 6 month period per patient was 5.3 m.c. as compared to 6.7 m.c. per patient for the same period as quoted b~¢ Lawrence (1955) using a multiple small dose te'chnique. In the present series the dose of 32p per patient was only 6.6 m.c. at 18 months. It is not clear why some patients with polycythae-

VERA

297

mia vera are resistant or completely refractory to radiation therapy. Failure to respond to 82p has been attributed to the severity of the disease as reflected by a white count of over 25,000/Cmm.; a spleen size more than 10 cm. palpable below the costal margin or a palpable liver; failure of the platelet count to fall below 100,000/cmm. or previous x-ray therapy (Wiseman et al., 1951; Abbatt et al., 1954; Verel, 1958; Calabresi & Meyer, 1959). In the present series none of these factors appeared to modify the response to ~zP therapy and analysis failed to show any relationship between the dose response and the lean body mass. Individual variation to therapy, therefore, remains unexplained. In spite of the difficulties in making an accurate 3~p dose prediction in the individual case, these results suggest that the correlation of isotope dose and absolute fall in R.C.V. has provided a useful scale for the prediction of a~P dosage on the basis of an absolute increase of R.C.V. Until recently, there has been much speculation regarding the incidence of terminal acute leukaemia occurring in certain cases of polycythaemia vera and its possible relationship to radiation therapy. The increased incidence of acute leukaemia has been attributed to a longer patient survival since the introduction of radiation therapy. However, Modan & Lilienfeld (1964) reported on a series of 1,222 polycythaemic patients followed up between 1937 and 1953 and claimed that the incidence of acute leukaemia increased with increasing exposure to radiation irrespective of the duration of the disease and Perkins et al. (1964) found no cases of acute leukaemia in 127 patients studied over the past 26 years managed without radiation therapy. The last authors also noted that the median survival of their non-irradiated group, 13-6 years, was no different from that of another reported series, 13-3 years, treated with 32p (Berkson & Gage, 1950). The use of 32p has certain considerable advantages in the management of polycythaemia vera. It is easily administered to outpatients and less medical supervision is required than with drug therapy, an important point when the patient does not live near a large medical centre. In the elderly patient, the statistical hazard of acute leukaemia may not outweigh these advantages when compared to the alternative of drug treatment. All these considerations suggest that radio-phosphorus will still find a place in the management of this disease. Because of this, it is important to introduce modifications of this well tried technique, which will enhance the effectiveness and decrease the potential hazards. The modifications outlined above may make such a contribution.

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CLINICAL RADIOLOGY

Acknowledgements--We thank Dr. H. E. Hutchison, Department of Haematology, Western Infirmary and Dr. R. A. Robb, Mitchell Lecturer on Methods of Statistics, University of Glasgow, for their help in these investigations. The work was aided by a grant from the British Empire Cancer Campaign. REFERENCES ABBATT, J. D., CHAPLIN, H., DARTS, J. M. M., & PITNEY, W. R. (1954). Quart. J. Med., 23, 91. BERKSON, J. & GAGE, R. P. (1950). Proc. Mayo Clin., 25, 270. CALABRESI, P. & MYER, O. O. (1959). Ann. intern..Med., 50, 1203. DACtE, J. V. & LSwls, S. M. (1963). Practical Haematology, 3rd ed. London: J. & A. Churchill. HARMAN, J. B., HART, P. L. DE V. and LEDLIE, E. M. (1955). Brit. reed. J., 1, 930. HUMS, R. & GOLDBERG, A. (1964). Clin. Sci., 26, 499. HUMS, R. & ROBS, R. A. (1965). Unpublished data.

LAWRENCE, J. H. (1940). Radiology, 35, 51. LAWRENCS, J. H. (1955). World Conference on Atomic Energy, A/Conf. 8/P/183. LAWRENCE, J. H. (1955). Polycythaemia--Physiology, diagnosis and treatment. Modern Medical Monographs. p. 47. New York, London: Grune & Stratton. MODAN, B. & LILrENFELD, A. M. (1964). Lancet, 2, 439. MULDOWNEY, F. P. (1957). Clin. Sci., 16, 163. NADLER, S. B., HIDALGO, J. V., & BLOCH, T. (1962). Surgery, 51, 224. PERKINS, J., ISRAELS, M. C. G., & WILrdNSON, J. F. (1964). Quart. J. Med., 23, 499. REINHARD, E. H., MOORE, C. V., BIERBAUM,O. S., ~; MOORE, S. (1946). J. Lab. din. Med., 31, 107. VeREL, D. (1958). Quart. J. Med., 27, 27. WISEMAN, B. K., ROHN, R. J., BOURONCLE, B. A., & MYERS, W.G. (1951). Ann. Intern. Med. 34, 311. W~TTS, LJ., (1956) IN PRICE'S TEXTBOOK OF THE PRACTICE OF MEDECINE. 9th EDITION. OXFORD.

BOOK REVIEW Pathology of Bone. By DOUGLAS COLLINS. (pp 248; 116 Fig; 72/6) London : Butterworth & Co. At the time of his death in 1964 Professor Douglas Collins had written the first ten chapters and part of the eleventh chapter of his book which he had planned to Cover all aspects of bone pathology in a full treatise of twenty-four chapters. His friend and colleague, Dr. O. C. Dodge has now prepared a final manuscript for publication by completing the eleventh chapter on some bone infections and has written chapter twelve, on Paget's disease of bone, based on the ample notes on the subject left by Professor Collins. The remaining twelve unwritten chapters were intended to cover the dysplasias and tumours of bone. This book there-

fore, is regrettably incomplete and deals only with the nonneoplastic conditions of bone. As one has learnt to expect from Collins' previous writings, the text is concise yet lucid, highly informative and a real pleasure to read. The illustrations are relevant to the text and of a high standard. This book will undoubtedly prove of immense value to Pathologists, Radiologists and all Clinicians whose work brings them into contact with bone disease. This publication is a worthy memorial to the late Douglas Collins and I am delighted that the publishers decided to print this work even in its incomplete form. My real and lasting lament is that Douglas Collins' lifelong work and thoughts on Dysplasias and Tumours of Bone will now never appear in print. A . D . THOMSON.