Radium therapeutics

Preface

In this little book I have tried to place before the profession a brief and clear account of the action and uses of radium and its rays. In the present limited state of our knowledge of the therapeutics of this substance and with new uses for it arising every few weeks, I have endeavoured to distinguish between ascertained facts and results which have not been definitely proved. This is my excuse for the com- | paratively scanty information furnished on some points.

I tender my most grateful thanks to Professor Makower for kindly reading through and revising Chapter I.; to Dr. Knox and Mr. C. E. 8. Phillips for their great assistance in reading through the manuscript and suggesting various alterations and improvements ; to Dr. Wilham Hill for hints on the pages on the cesophagus and for his kind loan of the blocks for some of the illustrations; and to Miss B. Temple Orme for kindly reading through the proofs.

The beautiful photo-micrographs in Chapter IIT. were kindly made for me by my friend, Mr. H. Lloyd Hind of Burton-on-Trent, from sections in my possession; to him also I tender this expression of my

gratitude.

: N. 8. FINZI. 107 HaRLEey STREET.

“wir - oak > ee ’

AEE

Contents

. INTRODUCTORY . INTERNAL ADMINISTRATION OF RapIuM .

LOGICAL ACTION OF RapDIUM RADIATIONS

. APPARATUS AND MeEtTHopsS OF APPLICATION

APPENDIX—OTHER RADIO-ACTIVE SUBSTANCES

Index

PAGES

1-12

13-27

28-47

48-60

61-75

76-102

103-107

109-112 oe - : — - —= is : iw « aa yas > - > 7 : - oie ~45= [> 2A? Or Pad & Pa ep ee ey ie oe 4 Fae Pt ™s : Z =. ® [666 Be oe | an ee, 8 OP nn ae 7 a.

v

Chapter I Introductory

Ir is essential, in order to understand the principles of the different methods of application of radium and the reasons for the employment of these methods in various diseases, to have a very clear outline of the physics and chemistry of this substance. The actual mechanism of its physiological action is often most obscure, but without a slight knowledge of the various products that constitute “radium” the obscurity would become absolute darkness.

Radium (symbol, Ra) is a metal which was first isolated from its compounds by Madame Curie in 1910, though its existence had been discovered some dozen years before by Monsieur and Madame Curie following some work by Becquerel on radio-activity.

Its atomic weight 1s 2265, and it falls into the same group in the periodic table as calcium, strontium, and barium, which it resembles in its chemical reactions. It isa bright white metal which rapidly tarnishes if exposed to the air and decomposes water. It combines powerfully with the halogens and acid radicles, forming stable compounds the chemical behaviour of which

I resembles that of salts of the alkaline earths. In one way, however, radium differs very materially from the other alkaline earth metals, and that is in possessing the property of radio-activity; all its compounds have this and in proportion to the amount of the metal they contain. With this property is associated the production of helium, which will be discussed presently.

By radio-activity we mean the property of certain substances of giving out spontaneously rays which will affect a photographic plate, cause florescence in certain substances, and render air a conductor of electricity by “ionising” it. In the case of radium, the metal itself gives out rays but it also gives off continuously a radio-active gas called the “ emanation.” + Therays from radium itself have been shown to be particles the size of atoms carrying a positive charge and are known as the a-particles: it seems probable that they are due to an actual breaking down of the radium atom, the emanation being the one product, with an atomic weight little below that of radium, and positively charged atoms of helium, with an atomic weight of 4, the other. The atomic weight of the emanation is of course 222°5 (226°5 minus 4), owing to the atom of helium the radium loses: its production goes on at a constant rate, the amount produced depending solely on the amount of metallic radium. It is estimated that half the radium will have decayed in two thousand years, half the remainder will have decayed in another two thousand, and so on. The greater part of the emanation can be obtained from a solution of a radium

1 Sir William Ramsay has given the name “nitcn” to this gas.

INTRODUCTORY 3 salt by bubbling air through it or by pumping the gas out of the solution by a vacuum pump. Water, in contact with an insoluble’ radium salt, will also take a certain quantity of emanation into solution, though a considerable part will remain locked wp in the salt. The emanation can be obtained in a state of purity either by heating the chloride to redness and condensing the emanation by means of liquid air, or by extracting the gases from a radium solution kept in vacuum, exploding the oxygen and hydrogen ' formed by the decomposition of the water by the radium dissolved in it, drying the resulting gas and condensing the emanation from this.

The emanation, like the parent substance, gives off a-rays, and again there is a formation of helium and of another substance of high atomic weight, this time a solid, known as radium A. This breaking down, like the formation of the emanation, goes on at a constant rate. If the emanation is separated from the radium, half will be converted into radium A in 3°85 days, half the remainder in a further 3°85 days, and so on. Radium A again breaks down, giving off a-particles and is transformed into radium B, which is then further converted into radium C; this last transformation, however, 1s associated with the production of different particles known as f-rays, which have a negative charge and are only +7ooth the size of the a-particles. It has lately been shown that radium itself also gives off some #-particles. From radium C there are both a- and #-rays, and, in addition, another radiation known as y-rays. There is still considerable doubt as to the nature of these,

1 An excess of hydrogen occurs for some unknown reason, one theory holding that they are not particles at all, but ether disturbances similar to X-rays: on the contrary, Bragg holds the view that both they and X-rays are corpuscular. These y-rays are generally, perhaps always, associated with 8-rays, but whether the converse is true is not quite certain. The next substance, radium D, was at one time thought to give off no rays which could be detected by the ordinary means, but has now been shown to emit 8-rays of comparatively low velocity. Further transformation products are radium E and radium F. The last is identical with polonium and gives off a-rays only. What is left after this is not yet known, but it is believed to be lead. It is extremely likely that radium itself is derived from the decay of another radio-active substance, uranium, there being at least one intermediate body, onium. One fact very strongly in favour of this is that all uranium ores contain radium approximately in a definite proportion to the amount of uranium present. The formation of radium from ionium has been proved.

These changes are shown in the following table :—

Time to fall to half value. Radiations.

Radium: 7. ; : About 2000 years. a and £. Emanation : : 3°85 days. a.

Radium A. ; : 3 minutes. a.

Radium B. : ‘ 26°8 minutes. 8B and y. Radium C. : ; 19°5 minutes. a, B, aud y.

(Radium C? . : 1'4 minutes. B).*

Radium D : : 16°5 years. Slow £.

Radium E, : ; 5 days. B and y.

Radium fF’. , 136 days. a.

* Occurs in small quantities and is probably a branch product.

THE RADIATIONS 5

If radium is sealed up until the amount of the transformation products, which are formed, 1s counterbalanced by the amount which decays, it 1s said to be in equilibrium. Its activity, especially that of the B- and y-rays, 1s then mostly due to the emanation and its subsequent products: radium itself accounts for 25 per cent. of the total a-ray activity. The emanation can therefore be separated from the radium and used for therapeutic purposes. Owing to the slow decay of radium D, it accumulates and there is a very slight increase in activity of a sealed-up radium salt which goes on for over two hundred years before equilibrium is established.

ithe wnt OL emanation is: the “curre,” and: is the amount in equilibrium with one gram of pure radium (metal). A miullicurie is the thousandth part of this.

THE RADIATIONS

THE a-RADIATIONS

These, as has been mentioned, are atoms and carry a positive charge. They travel with a great initial velocity, but owing to their comparatively large mass they are easily stopped, 7 cms, of air, => mm. of aluminium, or a sheet of thick note-paper being sufficient to reduce the speed of the most penetrating of them to a sufficient extent to prevent their presence being recognised. In most forms of apparatus these radiations are absorbed completely or to a large extent by the vessel containing or varnish covering the radium salt. They are deflected by a very strong magnetic field, owing to the positive charge they carry. The distance the a-particles will penetrate a given gas and still continue to ionise it 1s known as their range for that gas. The ranges in air of the a-particles from radium, the emanation, radium A and radium C respectively, are 3°50 cms., 4:35 cms., 4°82 cms., and 7:08 cms.

THE 8-RADIATIONS

The @-rays are also. particles but of much smaller size, and besides being projected with about ten times the velocity of the a-rays, their small-mass helps to make them much more penetrating: the velocity of the fastest of them is almost equal to that of light. As they are negatively charged they are deflected by a magnet in the opposite direction to the a-rays. They have a varying power of penetration; 75th mm. of lead will cut off quite a large proportion, but some of the rays will get through 1 or 2mm. of lead. There is a strong resemblance between them and the cathode rays of an X-ray tube. The different metals cut off an amount of f-rays that varies with their specific gravity.

THE y-RADIATIONS

The y-rays have enormous penetrating power and some will, in fact, go through a foot or more of lead while an inch only cuts them down to half. They were believed to be ether vibrations, though this had not yet been proved, and Bragg’s hypothesis that they are corpuscular has many adherents: they are not deflected by a magnet, and they strongly resemble X-rays but are very much more penetrating.

Until recently it was believed that none of these ravs are either reflected or refracted, but when the

THE RADIATIONS a.

8- or y-rays pass through any substance they cause it to give off secondary radiations. with properties which are to some degree dependent on the substance used and which may differ from the primary radiations both in absorption and nature of the rays; thus, when the y-rays strike a mass of lead, this metal gives out rays similar to both the 8 and y, but without their great penetrating power; roughly, the secondary radiation from lead is about half absorbed by + mm. of aluminium, ard so is equivalent to very soit X-rays.

All these radiations possess the power of ionising gases and so discharging a charged electroscope; they also have the power of accelerating chemical changes. For instance, they will cause to oxidise an aluminium vessel in which the radium is contained, whereas in the ordinary way this metal is hardly affected by the air.

It will be seen that if radium be sealed up in a glass tube the a-particles do not get out unless the walls of the tube are exceedingly thin, while the #-particles do; so, if the a-particles are retained, the radium in the tube will, if the insulation be good enough, gradually acquire a strong positive charge. If, now, it 1s required to open this tube and a file mark 1s made on the glass, a spark may pass from the radium inside to the file, and as the radium has caused the decomposition of the water vapour in contact with it into oxygen and hydrogen there will be a small explosion which will scatter the precious salt. This actually happened to two small tubes belonging to the author, and Abbé of America has recorded the spontaneous explosion of a glass tube, probably due to a similar cause. The danger can be obviated by sealing a platinum wire into the glass tube in which the radium is to be placed.

Tue SEPARATION OF THE RADIATIONS

The a-radiations can be isolated by using radium F, also known as polonium, which gives off a-particles

Fic. 1.—Diagram of Apparatus for Isolation of f-rays.

only. Fortunately, this is separated readily by chemical means from the rest of the radium transformation products. It has not yet been employed therapeutically.

The f@-rays cannot be completely separated from the y. If a thin filter, such as =5th mm. of aluminium, be employed to cut off the a-rays only, a mixture of B- and y-rays is left in which the 8 are in sufficient amount to dominate the therapeutic result. In such a

THE. RADIATIONS 9 mixture the total heating effect of the y-radiation is greater than that of the 8: the statements of some French writers that the @-rays predominate in the proportion of 10 to 1 is due to the fact that they have measured the ionisation caused by the rays and have used for this purpose an ionisation chamber which allowed the y-rays to pass through unabsorbed. For experimental purposes a preponderance of §-rays might be-obtained by using a powerful magnet to deflect the @-particles having the radium in a well in a thick lead case (Fig. 1).

The y-rays can be isolated by using a filter of metal which is sufficient to cut out all the 8-particles. Two millimetres of lead is enough to effect this, and, of course, also absorbs all the a-particles. Outside this must be used some substance of low atomic weight to absorb the secondary radiations given off by the metallic filter.

SECONDARY RADIATIONS

When either the 8- or the y-rays strike a block of © metal or other substance of high density they cause this to give off what are known as secondary radiations. It is not proposed to enter into the nature of these, but it will suffice to say they are less penetrating than the radiation which produces them. Fig. 2 illustrates a simple experiment to demonstrate the presence of these and their absorbability. A photographic plate wrapped in light-proof paper was placed film downwards on a lead cylinder closed at the farther end (half the case used for carrying one of the radium tubes), a triangle of aluminium 0°25 mm.

thick being placed between them to test the absorbability of the radiation. A tube containing radium, surrounded by a platinum filter, 2 mm. thick, was then sus- pended over the back of the plate for a few minutes. It will be seen that, though the plate is slightly affected by the radium, the secondary radiations from the circle of lead

Fic. 2.—Diagram of the Method of demonstrating Secondary Radiations.

have produced a much greater effect, while the aluminium has absorbed about half of these radiations

PHYSICAL CONSIDERATIONS AFFECTING TREATMENT

The rays are given out in all directions, they are neither reflected nor refracted to any appreciable extent, and so, apart from secondary radiations given off from the radium apparatus, the only substances which influence their action are those between the radium and the patient. Recent work has

THE RADIATIONS iil demonstrated the refraction of X-rays by crystals and their reflection by mica, so that our views about radium rays may need to be altered in the future. The maximum effect, then, will be obtained by having the radium surrounded by the tissues on which it is desired that its rays should act, and for this it 1s

Fic. 3.—The Action of the Secondary Radiations on a Photographic Plate.

necessary that it should be placed in a tube. On the other hand, for acting evenly on a surface it 1s preferable that the radium should be evenly spread on a flat applicator and the radiation from one side of it only is used.

If the source of radiation is a point, the intensity of the rays varies inversely as the square of the distance. This law is almost true for the small tubes that are a in practical use; in these the radium salt should be compressed into the smallest possible space and is almost a point. The amount of radiation is entirely dependent on the amount of metallic radium present and the thickness of the substances the rays have to traverse. It is obvious that in very impure specimens the impurity will itself act in some degree as a filter: this hardly affects the y-rays, but even if these alore are used, there is the very serious disadvantage that an impure salt takes up more room and is not able to be contained in so compact an apparatus.

It is possible, though it is not economical, so to use the radium that the rays from an enormous quantity can be made to radiate from a point the size of a pin’s head: if, for stance, the emanation from a gram of radium is drawn off by a vacuum pump from a solution of the chloride,’ dried, and then condensed in a small vessel, immersed in liquid air, this will in a few hours give off a radiation almost as active as that from the original radium ; its strength, however, will gradually diminish, falling to half value in 3°85 days.

‘In a flat applicator, on the other hand, it may be an advantage to have the salt somewhat impure, as this makes it more bulky and it can then be more easily spread over a large area.

When a sheet of metal or other substance is used to cut off a portion of the radiations, this is usually known as a filter or screen.

1 The emanations may also be obtained by heating the salt to redness.

CHAPTER II Tuts falls into two distinct methods

1. The internal administration of radium itself.

2. The internal administration of the emanation.

As will be understood from Chapter I., practically

all the properties of radium which are medically useful can be obtained from the emanation, with, however, the very great difference that the action is evanescent because the emanation decays much more rapidly than a radium salt.

INTERNAL ADMINISTRATION OF RADIUM SALTS (a) By the Mouth

The toxicity of radium salts administered in this way is not known, as it is far too expensive a substance with which to perform these experiments. There is no doubt that, if a sufficiently large quantity were used, it would be intensely irritant, and the actual contact with the mucous membrane of the stomach for the length of time it remained in that organ would cause severe burns to develop. Bellingham-Smith! has worked out the distribution and excretion of radium in the organs of mice. Even when injected subcutaneously, the majority is excreted by the small and large

1 Bellingham-Smith, Quart. Journ. Med., vol. v., No. 18, p. 249,

TS intestines and about 10 per cent. by the kidneys. In the distribution in the system, the notable fact is the comparatively high radio-activity of the kidneys and lungs. The accumulation in the latter 1s suggested. to be due to an attempt by the organism to get rid of the emanation which is excreted largely by the lungs. The radio-activity of the tissues diminishes rapidly but does not entirely disappear for several days. There is no evidence in mice that the liver or the skin plays any part in the excretion.

In practice, radium salts are not given internally as they can be so efficiently replaced by the emanation, and that without any loss of the parent substance, whereas if the radium salt were given by the mouth it would either be impossible to recover it or the difficulties of doing so would make the administration an extraordinarily costly one. An exception must be made in regard to the waters of Kreuznach, which contain minute quantities of radium salts. We may leave the discussion of this method of treatment with the remark that, in the administration of radium by the mouth, all the effects of the emanation must be obtained, in addition to any effects the radium itself may have, owing to the fact that the emanation is continually given off from the radium: the action is therefore spread over a long period while the radium salt 1s being slowly excreted.

(6) By Injection

Owing to the excretion of radium salts by the intestine,' the hypodermic or intra-muscular injection 1 Bellingham-Smith, loc. cif.

of a soluble salt would have some advantages over administration by the mouth, as the solution would have to be carried into the blood before it was eliminated. The injection of an insoluble salt of radium seems to have many possibilities: though it retains a good deal of the emanation in itself, it will continually be setting free a proportion of its total amount of emanation which is carried into the body. The radium salt itself will constantly be exerting the action of its rays and those of the active deposit (from the emanation entangled in it) on the part with which it 18 In contact, and it 1s found that, as these insoluble salts are absorbed extremely slowly, the action will proceed over a considerable period. This method has been used in the treatment of rheumatoid arthritis ! by injection into the affected joint, and it has also been used for injection into the substance of growths, but this latter method has not given very successful results.

(c) By Lonisation

This is a very complex subject, for it. must be remembered, in the first place, that the imtroduction of a substance in the ionic state will not have the same effect as the introduction of that substance in the form of a salt. Haret* has shown that radium ions can be driven deeply into the tissues, and that they are not deposited in the corium as might be

1 Chebrier, ‘‘ Treatment of Rheumatism with Insoluble Salts of Radium,” Gaz. d. hép., Paris, May 17 and 19, 1910, tome Ixxxiii., No. 56, p. 807; Presse méd. belge, Bruxelles, July 16, 1910, No. 57, p. 552; Arch. @ Electricité Médicale, June 10, 1911.

2 Haret, Compt. rend. Acad. de Sc., Paris, 1911, tome clii., pp. 800-802 ; also Béclére, Acad. de Méd., Paris, 1911 (3), tome Ixv., pp. 563-576.

expected from an analogy with calcium salts. It is a costly method, as the radium introduced is practically lost, and probably this accounts for the very small amounts which have been used in the experiments. Haret claims good results in the treatment of malignant growths by this method, but he used extremely small quantities of radium—small fractions of a miligram; and it is quite possible that, had he used larger quantities, his results might have been even more successful. He claims that the radium is carried into the tissues to a depth of even 9 or 10 cms., but 1f the amount of radium was estimated by the radio-activity, the possibility of the radium itself only going into the skin and the emanation and active deposit being carried into the deeper tissues has always to be considered: whether the active deposit can be ionised and introduced in this way is not known, as its chemical properties are not thoroughly determined. Radium C probably can, as it is possible to deposit it electrolytically from its salts, and the same is also probable in the case of radium D, EK and F, but one may safely assert that it is impossible to drive in the emanation itself, for it is chemically an inert gas forming no combinations, and therefore the solution of it will contain no ions.

INTERNAL ADMINISTRATION OF RADIUM HKMANATION (a) By the Mouth

This method is now being very largely used, especially in Germany, but generally with extremely

1 Finzi, “‘Some Experiments with Ionic Medication,” Brit. Med. Journ., London, Nov. 2, 1912, minute quantities: one frequently hears of quantities as small as 1000 Mache units or less. One Mache unit = 49x10"? Comes, and «a Curie is .the amount -of emanation in equilibrium with | gram of radium: from this it can be deduced that 1000 Mache units are approximately the amount of emanation in equilibrium with 20 mgrm. of radium. Now the emanation from 200 mgrms. of radium has been used in the treatment of disease, and though when this emanation is drawn off daily it corresponds only to that obtained from about 25 to 30 mgrms. of radium in equilibrium, it will be seen that its activity will be about 40,000 times as great as that mentioned above. But the extraordinary fact is that these very small quantities, nevertheless, exert an effect upon the human body. It may be mentioned here that the waters of Gastein, the strongest natural radio- | a active spring, contain less than 250 Mache units per litre.

It will not be overlooked that in this treatment there will be substances circulating in the blood which will give off a large amount of a-rays, an amount, in fact, which will be ten times as great as that of the B-rays : it 1s probable that these a-rays have an effect different from the other rays of radium, and differences have been shown by certain experiments in which the total rays were used, firstly alone, and then with the a-particles screened off. In external methods of treatment by radium these a-particles never get through the outer epidermis, and consequently do not exert any influence, but when the substances generating them are being carried about in the blood stream there will be no impediment to their exerting their 2 full power. The emanation is soon excreted, chiefly by the lungs, so that, if taken internally, it is removed a very short time after it has entered the blood stream. Thus, if a solution 1s swallowed with a meal, it is not entirely absorbed from the stomach for nearly four hours and it 1s completely eliminated in about four hours. After the emanation has disappeared, however, there will still be the active deposit (Ra A, B, etc.) in the body that has formed as a result of the decay of the emanation, and how long this persists or how it is excreted is not yet determined, as so few experiments have been made with a large enough amount. Although the emanation only decays to half value in four days, yet all trace of it has disappeared from the body in a few hours, showing the rapidity of its elimination.

The methods of preparing the solution are as follows :

1. The best way is to have a radium salt in solution, and, by means of a mercury pump, to withdraw the emanation every day. As the radium will have decomposed some of the water in which it is dissolved, the emanation will be mixed with a quantity of oxygen and hydrogen gas, but this can easily be removed by having two platinum wires sealed into the vessel in which the emanation is collected and passing an electric spark between them, which at once explodes the oxygen and hydrogen so that only the emanation is left :* this is then dissolved in water and kept in a bottle with a tightly fitting stopper for use during the day. The emanation being a gas with a high density is much more soluble than lighter gases, such as the gases of the atmosphere, and so can be dissolved in a

1 A slight excess of hydrogen occurs from some unexplained cause, comparatively small quantity of water. The bottle containing the emanation solution should be full and be kept inverted in order that there may be no danger of air leaking into it and gradually displacing the emanation from the solution, It has been shown that when administered by the mouth the emanation is excreted in four hours; it will therefore be advisable to administer the solution of the emanation in frequent small doses, but it must be borne in mind that it will not keep, as it falls to half strength in 3°8 days. 2. The radium in the form of an insoluble salt mixed with some other in- | soluble substance is contained in a porous earthenware pot, and this is placed in a glass vessel containing a comparatively large | quantity of water. Into the stopper of this is fitted 7 a second vessel so that a Fic. 4.—Emanation Apparatus, certain definite quantity of oe water 1s drawn off every day and replaced by filling the upper reservoir; by this means the amount of water in contact with the radium is kept constant (Fig. 4). This method is a wasteful one, for, as has been pointed out, insoluble salts of radium retain a large quantity of emanation within the granules of the salt. It is, however, an extremely simple and convenient method, and one which any one can manipulate. An even

Fia. 5.—Emanation Apparatus, method 3.

better way would be to filter the water through a quantity of powdered pitchblende concentrate. It seems probable that by this method the radium is gradually but very slowly dissolved in the water. If the carbonate 1s used, care should be taken to use only recently boiled water, so as to avoid any carbon dioxide which might form a soluble bicarbonate analogous to that of calcium.