radiotherapy cancer - postgraduate medical journal · (i) the physical basis of radiotherapy...

May, I946 RADIOTHERAPY AND CANCER 127

attacks is the most important feature of thetherapy. The relationship of upper respiratorytract infection to the catarrhal state must beemphasised, but this does not constitute the wholepicture which is that of a generalised respiratorycatarrh.

Summaryi. The pathogenesis and clinical features of the

catarrhal child have been fully discussed.2. The bronchoscopic findings in these children

have been described.3. The role of upper respiratory tract infection

in the catarrhal child has been stressed.4. A new therapeutic programme for the catar-

rhal child has been suggested.

5. The results of this new therapy, with reportson six illustrative cases, have been given.

REFERENCESI. DELLER, F. C. (1946), Post-grad. med. J., 22, 43.2. MONCRIEFF, A. (I934), "Diseases of Children," Garrod, Batten, Thurs-

field and Paterson, London, p. 4I3.3. GRIFFITHS, IVOR (I937), Lancet, ii, 723.

The great encouragement and help both academicand practical which I have received from Mr. J. D.McLaggan, F.R.C.S., and Mr. Ivor Griffiths,M.S., F.R.C.S., must not be overlooked, for withoutthem much of the understanding of the catarrhalchild which I believe I have now, would have beenlost to me. Much has been learned also from myanaesthetic colleagues, especially Dr. G. Hochs-child and Dr. Woodfield Davies who have so oftenborne with me very patiently.

RADIOTHERAPY AND CANCERBy D. W. SMITHERS, M.D., D.M.R.

(Director of the Radiotherapy Department of the Royal Cancer Hospital (Free) and the Royal Pree Hospital;Radiotherapist Brompton Hospital for Diseases of the Chest, and the West End Hospitalfor Nervous Diseases.)

IntroductionFifty years ago in November, I895, Wilhelm

Conrad Rontgen discovered X-rays; within oneyear Henri Becquerel had discovered radioactivity,and within three years Marie and Pierre Curie hadisolated radium. Rontgen, Becquerel, and theCuries opened up new fields for research and theirdiscoveries have had the most profound influenceon the progress of science. One direct outcome oftheir work was the introduction to medicine of avaluable new method of treatment, but there isprobably no type of treatment that has such awide application and has been used for so longwhich is so little understood or its value so littleappreciated by the general body of medical men.

Radiotherapy is the use of certain types ofionising radiations in the attack upon disease.Its most important, though by no means only,use in medicine is in the cure and the relief ofsuffering due to the scourge of cancer. A scourgebecause, although it is a curable disease in itsearly stages, it is responsible for the death of moreadults than any other condition, except heartdisease, and because it is second to none in itscapacity to produce fear and suffering.

(i) The Physical Basis of RadiotherapyRadiation is a process of transferring energy

from one place to another; radiotherapy appliesthis energy to living tissues which are abnormal

either in structure or in function. In cancertreatment it is employed to destroy malignantcells in such a way as to give the natural defencesof the body the maximum aid possible in dealingwith the disease and in repairing the damage done.The types of radiation in general use at the

present time are X-rays, produced at voltagesranging from about 50,000 to several hundredthousand volts, and the gamma rays and beta raysfrom radium. Beta rays are particles (electrons)and X and gamma rays are waves. These waves,however, behave very like particles in that theirenergy is concentrated in units (photons), theenergy in each unit depending on the wavelengthof the radiation-the shorter the wavelength thegreater the energy of the photon.To understand the application of these various

types of radiation in medicine it is necessary tostudv the underlying physical principles involved.These radiations affect matter, both organic andinorganic, in fundamentally the same way. Theyproduce changes in the atoms of the substancesthey irradiate, either by knocking electrons rightout of the atoms (ionisation) or, by displacingelectrons within the atoms (excitation). In eithercase the properties of the affected atom are changedand this change may initiate a whole series ofchemical reactions. With inorganic materials theresults of the irradiation may be slight, such as achange of colour of the material, but with biologicalmaterials the changes produced may be consider-

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128 POST-GRADUATE MEDICAL JOURNAL May, I946

able and-the death of living cells or even of wholeorganisms is a frequent sequel to irradiation.The spatial distribution of the energy absorbed

varies with the type of radiation, and the method ofapplication employed and these differences lead toconsiderable variations in biological effect. Thusthe various radiations each have their own field ofusefulness according to the condition to be treated.For example, the beta rays from radium producetheir effect in the surface layers of the materialirradiated but do not penetrate very far. Theyare therefore used for the treatment of very super-ficial conditions. On the other hand, X-rays pro-duced at high voltages have considerable pene-tration through the human body and are used fortreating more deeply-seated lesions.The progress in nuclear physics being made at

the present time is placing new instruments in thehands of the radiotherapist. Much work remainsto be done before the significance and value ofthese new discoveries in the treatment of cancerare fully appreciated. Neutrons, artificial radio-active substances, extremely high-voltage X-rays,and penetrating beta rays are becoming available,however, and some at least will offer new oppor-tunities to the radiotherapist and hope for furtherimprovement in the results obtained by radio-therapy.

Atomic StructureAn atom consists of a nucleus around which

electrons circulate. The nucleus contains nearlyall the weight of the atom and is positively charged.The electrons which weigh approximately i/i,850thof the weight of the lightest nucleus are negativelycharged. The number of electrons circulatingaround the nucleus is equal to the number ofpositive charges on the nucleus so that theyneutralise the charge on the atom.The simplest element is hydrogen which has a

nucleus composed of one positively charged particle,a proton, and one electron circulating round it(Fig. i). The next element in the periodic table(elements in order of increasing atomic weights) ishelium with two electrons, a nuclear charge of twobut with a weight four times that of the hydrogenatom. The helium nucleus is composed of twoprotons and two other particles, known as neutrons,of approximately the same weight as protons butcarrying no electric charge (Fig. 2). The atomswhen arranged in the periodic table and numberedhave nuclei on which the charge increases by oneunit as we pass from one atom to the next. Theatomic number indicates the size of the nuclearcharge (and therefore the number of electrons inthe outer atom). Lithium with atomic number 3has three electrons and a nucleus composed of 3protons and 4 neutrons (as its atomic weight is

ELECTRON

7( NUCLEUS

* 3

\r- '

FIG. I.-Diagrammatic representation of the hydrogenatom (,Hz). The diameter of the nucleus is approxi-mately 10 00 of the diameter of the atom. Themass of the electron is approximately l of themass of the nucleus.

seven times that of the hydrogen atom). Thenumber of neutrons is equal to the weight of theatom less the atomic number. All atoms of thesame substance do not have the same weight,however, and a hydrogen atom may have a massof two when its nucleus is made up not only ofone proton but with one neutron as well. Suchatoms with different weights but the same atomicnumber are known as isotopes, the heavy isotopeof hydrogen (deuterium) combined with oxygenforms "heavy water." Lithium has a light isotopeof mass six with three protons (atomic number 3)and three neutrons in the nucleus (Fig. 2).The most important characteristic of an element

is its atomic number. Elements are given chemicalsymbols and isotopes are shown by writing thefigures representing the mass above and after thesymbol; the atomic number is often written beforeand under the symbol. The two isotopes oflithium would thus be written 3Li6 and 3Li7,hydrogen 1H1 and heavy hydrogen jH2. Atomicnuclei are not altered in chemical reactions whichare the result of a re-arrangement of their outerelectrons in such a way as to link elements together.Isotopes are difficult to separate because theirchemical and physical properties are primarilydependent on their nuclear charge and although theydiffer in weight their nuclear charges are the same.



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May, I946 RADIOTHERAPY -AND CANCER 129

2He4 3L;7 3L16

OC PARTICLE ISOTOPESHELIUM NUCLEUS LITHIUM NUCLEI

IFIG. 2-Diagrammatic representation of Helium and Lithium nuclei.

The atom is a minute entity held together by avast amount of energy which renders it highlyresistant to attack. The electrons circulatinground the nucleus in the atom travel in certaindefined orbits (the method of wave mechanicsexpresses this more accurately in terms of a systemof waves surrounding a centre of force). Someelectrons travel in orbits close to the nucleus,others further away and others in the outer partof the atom. The heavier atoms have a largenumber of groups of electrons travelling in anumber of different orbits (Fig. 3). Electrons inthe atom can only travel in these orbits; they mayjump from one orbit to another or be knockedout of the atom altogether, but they cannot takeup some intermediate position inside the atom.An electron from outside may strike an electronin the atom handing over to it sufficient energyto move it from one orbit to another. Such anatom has gained energy and been altered to anunstable state. It will tend to revert to its normalstate and in doing so will give off the energy gainedin the form of radiation. If the energy change islarge the radiation will be of short wavelength(with large quanta or units of energy-photons).Each atom has its own set of energies for its variousorbits and when excited gives out radiations ofspecified wavelengths (characteristic radiation).A larger amount of energy is required to displaceelectrons from orbits close to the nucleus than fromorbits in the outer atom.

The Production of X-RaysAn X-ray tube consists of an evacuated glass

vessel containing a heated filament (the cathode)which is the source of electrons, and a metal target

(the anode) which is the source of X-rays (Fig. 4).A high electrical potential is put across the tubeso that the electrons from the cathode are speededacross the gap to strike the target. As theseparticles strike the target they are suddenlyarrested and their energy of motion is transformedinto electromagnetic energy (waves). The targetthus becomes a source of X-rays, mostly due tothe alteration in motion. of the electric chargewhen the electrons collide with the target, but alsopartly due to characteristic radiation resultingfrom the displacement of electrons from theirorbits in the atoms of which the target is composed.

CATHODE ANODE

FIG. 4.-Diagrammatic representation of an X-ray tube.The cathode filament is heated by a small electriccurrent and a high electric potential is put across thetube to speed the electrons across the gap to strikethe target. The sudden arrest of the electrons(cathode rays) when they strike the target results inthe emission of X-rays.

Spontaneous RadioactivitySome of the elements of high atomic number with

the most complicated nuclear structures (e.g.uranium, thorium, radium) undergo spontaneousdisintegration giving off radiation in the process.These rays consist of either alpha particles (massfour, positive charge two-the nuclei of heliumatoms-Fig. 2), beta particles (negative chargeone-electrons) or gamma rays (short wavelength



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130 POST-GRADUATE MEDICAL JOURNAL May, I946rays) which are an accompaniment of the emissionof alpha or beta particles. The gamma rays aremore penetrating than the alpha and beta rays,and as they are not charged particles they are notdeflected by electric or magnetic fields. When aradioactive element gives off an alpha particle itchanges to a different element with an atomicnumber lower by two and a mass lower by four;the emission of a beta particle increases the atomicnumber by one but leaves the mass of the nucleusunaltered. Some radioactive elements disintegraterapidly, others very slowly, the rate cannot bealtered and is expressed as the time it would takefor half the atoms initially present to disintegrate.This time (the half-life or half' value period) variesfrom a fraction of a second to millions of years(it is 3 82 days for radon and I,650 years forradium).

Artificial RadioactivityUntil recently the only radioactive materials

known were those found naturally and theirseparation and purification was a very laboriousand costly procedure. With new techniques andinstruments almost all the common elements cannow be produced in a radioactive form.The mass of a nucleus is slightly less than the

total mass of the protons and neutrons of which itis composed. It is now recognised that energyand mass are equivalent and that this slightdifference in mass is due to the energy required tosplit up the nucleus. Radioactive substances dis-integrating spontaneously give off particles fromtheir nuclei and this emission of particles is accom-panied by the release of the binding energy in theform of short wavelength radiation (gamma rays).It is possible to bombard atoms with particles sothat some of them will enter the nucleus giving itincreased energy and making it unstable. These

nuclei will tend to revert to their normal stategiving off the energy gained. This process isknown as artificial radioactivity as it is inducedin atoms that do not normally undergo spon-taneous disintegration. Neutrons are commonlyused for the induction of artificial radioactivitybecause they have no charge, do not interact withthe electric field and can therefore penetrate moreeasily to the nucleus where charge is concentrated(Fig. 5).

Particulate RadiationsThe particulate radiations obtained from radio-

active substances (alpha and beta rays) have littlepenetration, being stopped by thin layers of material.Alpha rays are absorbed in a few centimetres ofair or in a thin sheet of paper, and are thereforeof little use in treatment. Beta rays from radiumare sometimes used for the treatment of very super-ficial lesions for they are approximately IOOtimes more penetrating than the alpha raysemitted, but are still absorbed by quite thin layersof material such as 5 o mm. of aluminium. Specialapparatus is therefore necessary for the productionof high-speed particles if direct use is to be made ofparticulate radiations for the treatment of anybut very superficial tumours.High speed neutrons can now be obtained direct

in a form suitable for use in radiotherapy. Theinstrument which has made possible the productionof neutrons in sufficient quantities for use in therapyis the Cyclotron (Fig. 6), an apparatus designed byLawrence, for research work in atomic physics.It consists essentially of two hollow semi-circularelectrodes, known as Dees on account of their shape,which are placed between the poles of a magnet.A heated wire provides a source of electrons. Aminute quantity of heavy hydrogen gas is intro-duced which, when bombarded by these electrons,

PROTON ELECTRON

00

DEUTERON STABLE PHOSPHORUS RADIOACTIVE PHOSPHORUS STABLE SULPHUR(HALF VALUE PERIOD

14-2 DAYS)FIG. 5.-Diagrammatic representation of the production of artificially radioactive phosphorus by the bombardment of

stable phosphorus with deuterons. The neutron in the deuteron penetrates the phosphorus nucleus which;thenbecomes excited and gives off an electron so changing to stable sulphur.



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RADIOTHERAPY AND CANCER D. W. SMITHERS, M.D., D.M.R.

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FIG. 3.-Hypothetical structure of the radium atom as suggested by Niels Bohr prior to thedevelopment of wave-mechanics.

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FIG. 6.-Lawrence's 6o-inch, 220-ton Cyclotron at the University of California. Bombardment chamber seen at the edge ofthe Dee chamber between the poles of the magnet. The radiofrequency oscillating power supply to the Dees is seen atthe top on the left. (By courtesy of Dr. Paul C. Aebersold and the Editor of Radiology.)



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FIG. 7.-loo-million-volt Betatron. (By courtesy of Victor X-ray Corporation.)

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ON #h2; I eG. CeItFIG. 8.-Diagram showing the degree of radiosensitivity of chromosomes during the developmental cycle in

pollen grain (PG) cells. The most sensitive period is between 30-20 hrs. before metaphase and coincideswith the time of chromosome reduplication. (By courtesy of Dr. P. C. Koller.)



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A .. ..CFIG. 9.-Cell division in tumour cells (A) before and (B and C) after irradiation. The radiation induced fragments

are scattered and lost in the cytoplasm leading to the degeneration of the two daughter cells.(By courtesy of Dr. P. C. Koller.)

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FIG. I I.-Five-gramme teleradiumnunit with pneumatic trans-ference of radium to lead-linedsafe.



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RADIOTHERAPY AND CANCER D. W. SMITHERS, M.D., D.M.1

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FIG. I2.-Radiograph of radon seeds inserted into a carcinoma of the stomach.



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RADIOTHERAPY AND CANCER D. W. SMITHERS, M.D., D-.M.R.

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FIG. I4.-Siemens "contact" X-ray therapy plant.



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May, 1946 RADIOTHERAPY AND CANCER 137

loses some of the single electrons from the outerpart of -the atoms leaving the heavy hydrogennuclei (deuterons) behind. Particles in a strongmagnetic field travel in circular orbits so that thesedeuterons circulate between the poles of themagnet inside the hollow electrodes. The deuteronsare repelled by the positive Dee and attracted tothe negative Dee so that they are accelerated asthey pass on their circular course from one Deeto the other. An oscillating voltage is applied tothe Dees so that each time particles pass from oneelectrode to another they are given a furtheracceleration. As the particles gain speed theyspiral outwards taking a longer course but takingthe same time to complete each circuit. Theoscillating voltage is kept at a constant frequencyand a stream of particles in process of beingaccelerated spiral from the centre outwards gettingfaster as they go. The stream of high speeddeuterons is finally allowed to strike a berylliumtarget from which neutrons are then emitted.These neutrons may either be used directly fortreatment or for bombardment of other substancesfor the purpose of inducing artificial radioactivity.The other new instrument which will probably

become of great importance in therapy is theBetatron (Fig. 7) designed by Kerst. It is rathersimilar to a cyclotron though the method ofacceleration of the particles is different. Particlesin a cyclotron can only be accelerated to a speedmuch less than that of light so that only heavyparticles can be given great energy. The betatroncan accelerate light particles (electrons) till theyacquire very great energies. The electrons cir-culate in a doughnut-shaped vacuum tube placedbetween the poles of a magnet and are acceleratedby magnetic induction; the electromotive force iscontinually applied directly to the electron streamby a time-varying magnetic field. As the electronstravel faster the magnetic field is increased so thatthe electrons do not spiral outwards until theyhave reached their maximum speed, havingtravelled as much as 200 miles, and special orbitexpanding coils are energised. These coils supplya heavy reverse current which rapidly reduces themagnetic field and allows the electrons to spiraloutwards to strike a target and produce X-rays.By this means-X-rays have been produced at theequivalent of 50 million volts and a ioo-million-volt Betatron has now been constructed. Thebeam of electrons may one day be used directlyin treatment, but it is not yet certain whetherthis would be useful even if it were practicable.

The Absorption of Energy in TissuesWhen radiation is applied to a patient part of

*the energy in the beam is absorbed. It is only thatfraction of the energy which is absorbed that is

biologically active (Grotthus' law). The energy inthe particles, or in the photons of the X or gammarays, is handed over to electrons in the tissues bycollision. In these collisions a photon may handover all its energy to a tissue electron removingit from one of the inner orbits of an atom andsending it out with considerable velocity (photo-electron) the atom then reverting to its normalstate emitting further radiation (characteristicradiation) in the process. A photon may onlyhand on part of its energy to an electron (recoilelectron) and proceed on its way with changeddirection, less energy and so a longer wavelength(modified scatter), or it may merely be deflectedby an electron without loss of energy (unmodifiedscatter). The tissues are themselves, therefore, asource of X-rays (characteristic and scattered)which in turn hand on energy to further electronsuntil the energy absorbed is dissipated in intenseelectronic activity. Electrons are made to travelin the tissues with varying speeds for varyingdistances according to their energy (up to a fewmillimetres at most under existing therapeuticconditions, but possiblv up to io centimetres ormore with the Betatron) and are slowed down bycollision with other electrons which they removefrom molecules in their paths. A molecule thatlooses an electron becomes positively charged(positive ion) and an electron torn from one mole-cule attaches itself to another which then becomesnegatively charged (negative ion) the process beingknown as ionisation. It is the passage of anelectron through some sensitive area or the for-mation of an ion pair at a sensitive point in thetissues, which forms the basis of the biologicalaction produced by radiation.

(2) The Biological Basis of RadiotherapyIrradiation of living tissues causes damage.

The damage done depends on the amount anddistribution of the energy absorbed, the rate ofabsorption during exposure, the intervals betweensuccessive exposures, and the total period overwhich the whole treatmeAt is spread (the time-dose relationship); the sensitivity of the differenttypes of cell, and the stage of mitotic activityand duration of mitotic cycle in individual cells(the inherent cell sensitivity); and the state of thesurrounding tissues (sensitivity due to environmentand possibilities of repair).

Radiotherapy for cancer is the application ofradiation to the patient so that the energy absorbedis concentrated in the tumour, and is delivered insuch a way as to do an adequate amount of damageto the tumour with the least possible damage tothe normal tissues. For success this requires ahigh degree of precision in planning and adminis-



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tering the treatment both with regard to theamount and distribution of the energy absorbedand to the relationship of dose with time.The literature on the biological actions of radia-

tion is so immense that it has become very difficultfor the research workers in this field, let alone theradiotherapists, to summarise and absorb it. Theradiotherapist who wishes to apply the knowledgegained to the practical task of treating patientshas the problem further complicated for him. Heis not so directly concerned with the response ofisolated biological material, which is the basis ofmost of this research work, as he is with the effectson certain tissues, forming part of a whole organism,which cannot be irradiated in isolation. In cancer,where the main tissue to be irradiated is composedof cells differing widely in development andactivity and often abnormal both in structure andbehaviour, the practical application of experi-mental findings is especially difficult. Whatfollows is therefore an incomplete summary of theposition for no authoritative account either of therelative importance of the various time-doserelationships or of the sequence of biological effectsthat result from irradiation applied to tumours inpatients is yet possible.

Structural Changes in the Cell Nucleus Resultingfrom Irradiation

Much of the confusion that exists regarding theresponse of living tissues to irradiation is due tothe fact that many of the effects observed andmeasured are the results of a series of unknownreactions set in motion by the radiation. Eventhe mechanism by which individual cells areaffected by radiation is not yet understood com-pletely. It was shown over 30 years ago that thenucleus was the part of the cell most sensitive toradiation. There are probably many effects ofradiation on the cell that have yet to be discovered,however, and it may be that important changesare produced primarily in the cytoplasm. Livingtissues of any type can be killed by massive dosesof radiation no doubt due to non-specific chemicalchanges resulting from the large amount of energyabsorbed by the component cells, but lethal changescan also be produced by very small doses parti-cularly on cells that are just about to divide. Theresting nucleus has a homogeneous appearancewhich gives way to characteristic and complicatedstructure as mitotic activity commences. AsCrowther wrote "the correlation between theappearance of structure and abnormal sensitivityseems too close to be fortuitous."We have seen that the action of radiation on

tissues is discontinuous; the energy absorbed isconcentrated in a comparatively small number ofatoms. The "target theory" of the biological

action of radiation assumes that action takesplace either when an electron passes through asensitive spot or when an ion pair is formed atsuch a spot. In 1928 Muller showed that X-raysproduced gene mutations, an action on minutestructures situated on the chromosomes. This isan irreversible change dependent only on the dosegiven and quite independent of any time relation-ship. Stern in I929 produced evidence thatradiation could break chromosomes. Chromosomebreakage is one of the initial, fundamental, directeffects of radiation on cells which can be observedand analysed. It is a discontinuous effectoccurring at various points in the nucleus whichwe have seen becomes especially sensitive to thistype of damage as its characteristic structuredevelops. The chief method of measuring thedirect effect of radiation on cells is by assessingthe frequency with which these breaks are inducedin chromosomes. Chromosomes are most liableto radiation induced breakage at the end of theresting stage when they divide longitudinally intotwo chromatids (Fig. 8). The breaks producedmay effect one or both of these sister chromatids.An induced break may rejoin in the original posi-tion, may reunite in a different way with a sisteror non-sister chromatid or may remain open as asingle break. Breaks that are not reconstitutedin the normal way will result in abnotmalities inthe daughter cells as the damaged chromosomescannot migrate normally along the spindle andeither chromosome fragments will be left behindor chromosome bridges will be formed (Fig. 9).In both cases the resulting cells will be deficientin chromosome material and will die.

Chemical Changes Following Structural Alteration.Chromosome structure and cell activity are

beginning to be described in relation to thechemical processes taking place in cells. In I942Caspersson and Santesson by microscopical studies,microchemical analysis and ultra violet spectro-scopy of cells showed that intensive hyperfunctionof heterochromatin (a specific portion of thechromosomes concerned with protein synthesis,the basis of cell-growth) is characteristic of cancercells. They showed that abnormal chromosomebehaviour and increased division rate may beexplained in terms of disturbances in this systemwhich controls protein synthesis. Nucleic acidsare the agents of this synthesis in the cell andMitchell has shown that significant quantitativechanges are produced in nucleic acid metabolismby therapeutic doses of radiation. Koller, bycytological analysis of tumour cells, showed thatall their chromosome abnormalities and the in-creased rate of division itself might be explainedin terms of a quantitative change in the nucleic



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May, 1946 RADIOTHERAPY AND CANCER 139

acid synthesis which is assumed to be due toalteration in the heterochromatic region of thechromosomes. Radiation thus produces funda-mental changes in the structure of the sensitivenuclei of cells as a result of which the chemical cellprocesses, particularly those concemed with growth,are altered.

Effects of Variation in Dose-Time Relationship onCell Reaction

With irreversible actions such as the productionof gene mutations the change is independent oftime and depends only on the amount of energyabsorbed. With chromosome abnormalities, how-ever, the time relationship of dosage is important.The number of cells showing chromosome abnor-malities after irradiation at low dosage-rates is lessthan at high dosage-rates (Koller). Cell recovery(reunion of the induced chromosome breaks in thesame position) is favoured by delay in producing asecond injury in the same cell. Irradiation at highdosage-rates causes arrest of mitosis so that thetumour goes into a resistant phase whereas lowdosage-rates interfere much less with the progres-sive development of cells. High dosage-rates tendto produce many injuries in individual cells, oftenmore than are required to kill it, but also to producepermanent injury in a greater number of cells thanlow-dosage rates. The effects due to variation indosage-rate can also be obtained to some extentby fractionation of the dose (dividing the treat-ment into a number of exposures). Fractionationat high dosage-rates is particularly suitable forsurface tumours where the radiation does not haveto pass through normal tissues to reach the malig-nant growth. Low dosage-rates may be an advan-tage in the treatment of certain more deeply seatedtumours where the radiation must pass through theskin, though more work on this subject is requiredbefore this can be established or disproved. Thelong cell cycle in the basal layers of the skin and thelow dosage-rate both favour restitution of chromo-some breaks and recovery of the skin from damage.The low dosage-rate will also produce less per-manent injury to the tumour cells, but the relativeeffect for any given dose to the skin may be greaterwith certain types of tumour.

Effect of Variations in the Dose-Time Relationshipon Tissue Reaction

We have seen that therapeutic doses of radiationaffect primarily cells that are about to divide, thechief permanent result being degeneration anddeath of these cells manifested most clearly andmost rapidly through mitosis. In many tumoursadjacent cells frequently divide synchronously sothat radiation-induced degeneration often involvessmall volumes of tissue scattered through the

tumour mass. This irregular break-down of thetumour results in a gross disturbance of theorganisation of the neoplasm as a whole, withsecondary changes, such as alterations in bloodsupply, which may lead to further degeneration.The body responds with an attempt at tissue repair,with infiltration of defence cells, digestion andremoval of debris and the formation of fibroustissue. This normal tissue reaction plays an im-portant part in tumour regression and is initiatedby the radiation-induced break-down of cancercells. Further treatment given too soon, when themajority of the dividing cells present have beenaffected and the normal tissue reaction is at itsheight, may do more damage to the repair processthan to the tumour. Subsequent treatment giventoo late will either fail to maintain the rate of celldegeneration and so inhibit the normal tissuereaction, or allow the repair processes in parts ofthe tumour to progress too far before sufficientdamage has been done to the cancer cells. Fibrousstrands developing within the tumour substancemay cut off and protect islets of viable tumour cellsfrom invasion and digestion by defence cells.The timing of fractionated treatment may thereforebe an all important factor in the successful removalof malignant tumours, particularly the more resist-ant ones, as incorrect timing may give the massan increased resistance to further irradiation.

Radioresistance and RadiosensitivityThere has been much confusion caused by the

different interpretations placed on the term "radio-sensitivity." There is a wide variation in cellularradiosensitiveness, "a dose of only 40 r. will killhalf the individuals in a clutch of Calliphora eggs,whereas a dose of 330,ooo r. is required to produce50 per cent of deaths in a culture of Colpidium"(Crowther). Bergonie and Tribondeau in I906stated that the radiosensitivity of cells varieddirectly with their degree of proliferative activityand inversely with their evolution from embryonaltypes and degree of differentiation. The responseof a tumour to irradiation does not depend, how-ever, solely on the type of cells of which it iscomposed but also on the environment in whichit is growing-not only on histological structurebut also on site. The grouping of tumours histo-logically in order of rate of immediate tumourresponse to irradiation (the usual interpretation ofradiosensitivity) gives little information as tocurability and takes no account of the variation inresponse that occurs within recognised histologicalgroups or from one site to another. Squamous-cell carcinomata of the bucpal cavity undergocomplete regression following irradiation morefrequently than their metastases in the cervicallymph nodes, whereas the reverse is almost certainly



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140 POST-GRADUATE MEDICAL JOURNAL May, I946the case with adenocarcinomata of the breast andtheir deposits in the axillary nodes. Broders'grading of tumours according to their degree ofdifferentiation is a valuable guide as to the pro-bability of their early dissemination but, as hasbeen shown by Spear and Gluicksmann, provides noclear indication as to the likely response of theprimary tumour to irradiation. In fact if we take"radiosensitivity" to mean a favourable responseto radiation, it is often the more highly differen-tiated squamous-celled carcinomata that are themost radiosensitive.A lymphosarcoma composed of a mass of rapidly

dividing cancer cells with little supporting stromawill frequently show a dramatic initial response totreatment for with massive cell degeneration thetumour collapses, only too frequently to releaseviable cells to be carried to distant parts of thebody. An osteogenic sarcoma composed of cellswith a very different cycle and with a firmersupporting stroma will usually show no obviousimmediate clinical response to treatment at all,but there is some evidence that the cancer cellsthemselves are not so insensitive to irradiation asmight appear on superficial clinical observation.These two tumours require very different types oftreatment in so far as the time-dose relationship isconcerned. The tendency to deliver a higherdose in a shorter time the more resistant thetumour appears to be, is giving way to plannedfractionation of the dose to suit the individualrequirements of the tumour concerned accordingboth to its histological structure and to theenvironment in which it is growing.

(3) Radiotherapeutic ApparatusThe Radiotherapist should have available a

wide variety of apparatus designed to enable himto administer an adequate dose in the best possibleway to suit each tumour and to concentrate thisdose in the volume of tissue occupied by thetumour. For this purpose a large number ofdiffering types of radium containers, radon seeds,teleradium units and X-ray tubes are required. Inthe future greater use will almost certainly bemade of the Cyclotron either to provide artificialradioactive substances for injection or a beam ofneutrons. Betatrons should provide new oppor-tunities for the treatment of deep-seated cancerwith very penetrating X-rays where the maximumenergy absorption is below the surface and a highdose can be concentrated in the tumour moreeffectively than has been possible in the past.

- RadiumThe gamma rays from radium are applied to the

patient in one of three main ways. In the first

method the radium is enclosed in needles or tubesusually made of platinum of sufficient thicknessto cut off the alpha and beta rays (Fig. io). Theamount of radium in each needle rarely exceeds afew milligrammes and these needles are eitherinserted into the patient's tissues or are mountedin an applicator of wax or other similar materialwhich is fitted to the body surface. The needlesare left in position for the time necessary to givethe requiredKdose. Measurements of the radiationin the neighbourhood of these needles and tubesand planned arrangement on the surface, in thetissues or in body cavities, has transformed thistype of radium therapy which has recently becomefar more accurate and efficient chiefly as the resultof the work of Paterson and Parker. The secondgeneral method is to have a considerable quantityof radium, up to several grammes, in a containerand use this in the same way as an X-ray tube isused This is known as a teleradium unit or aradium "bomb" (Fig. II).

Teleradium units containing as much as I0grammes are now in use and larger units still arein preparation. It is probable that units of thistype will in future contain tubes of artificial radio-active elements with a long half-value period.Teleradium units have proved to be of value parti-cularly in the treatment of some tumours situateda short distance below the surface. This isespecially so in the region of the head and neckwhere the distribution of the energy absorbed iswell suited to the difficult problem of applyingmultiple small fields to an irregular curved surface.The third method is to use radon, a gas which is

given off from radium, and to enclose it in smallplatinum or gold "seeds." These seeds can beinserted into the patient's body and left there,for the radioactivity of radon disappears almostcompletely after a few weeks (Fig. I2). Radiumneedles on the other hand must never be left incontact with the patient longer than the calculatedtime to give the required dose since gamma rayswill continue to be given off indefinitely with noappreciable diminution in intensity (half-valueperiod I,650 years).

X-raysA radiotherapy department should be supplied

with a number of X-ray tubes generated at voltagesvarying from 50 kilovolts to 500 kilovolts or insome cases to I,000 kilovolts (Fig. I3) or more.This provides the radiotherapist with a range ofbeams of varying penetration to enable him toselect the most appropriate apparatus for eachpatient with which he has to deal. Low-voltageapparatus with the source of the X-rays placedclose to the skin is used for superficial lesions andadvances have been made in design of apparatus



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May. I946 RADIOTHERAPY AND CANCER 141

and application of such beams of X-rays by.Schaeffer,Witte, Chaoul, and Adam, this type of treatmentbeing known as "Contact therapy" (Fig. I4).

In recent years great improvement has takenplace in the accurate localisation in deep-seatedtumours of the energy absorbed from externalhigh-voltage X-rays and teleradium. This is aresult of Mayneord's work on three-dimensional orvolume distribution. An improvement in theresults of treatment to some deep-seated tumourspreviously regarded as almost outside the scopeof radiotherapy is now becoming manifest as theresult of this work. With increased penetration,improved means of tumour localisation and moreaccurate beam direction, further improvement maybe expected.

Artificial RadioactivityThe study of the properties of artificial radio-

active substances is proceeding rapidly togetherwith their application in the treatment of disease.They have a very important role to play in physio-logical research for radioactive atoms of variouselements can be followed in their progress roundthe body and used as "tracers." Spear wrote,"one radioactive atom in a million is sufficientfor the progress of the substance to be followedwith extreme accuracy by physical detectors andat this dilution no biological effects of the radio-activity can be detected. . . It is possible tomake radioactive isotopes of all the stable elements,and these isotopes behave identically with thecommonly obtained element both chemically andphysiologically. . . Radio sodium, given to apatient by the mouth as common salt, can bedetected by means of a Geiger counter within twominutes of administration in the finger tips."The production of fairly large quantities of rarestable isotopes of carbon (C13) and nitrogen (Nt5)which may be introduced into sugars or proteinsand followed with the help of the mass spectro-graph may also prove to be of great value in thestudy of metabolism.

In the treatment of malignant disease radio-active elements are being sought which will beselectively absorbed in certain tissues whereradiation is required. It is already known thatthe concentration of radio iodine can be raised inanimals to the point at which it completely destroysthe thyroid gland without affecting the para-thyroids. In man radio phosphorus 15p32 (Fig. 5)which is absorbed selectively in the bone, bonemarrow, spleen, lymph nodes, liver, and proli-ferating cells generally has been used for thetreatment of the leukaemias, lymphadenopathies,and polycythaemia vera. Radio strontium whichis selectively absorbed in bone is now undergoingclinical trial.

(.) Uses and Limitations of Radio-therapy for Cancer

Surgery and radiotherapy are still the onlyknown means of curing cancer. Much interestingwork on chemotherapy is being done but despitethe reports which appear in the lay press, the moresensational of which refer to the success of new"cancer cures'' and which are deprecated as muchby the serious workers in this field of researchas by anyone else, there is still no real evidencethat human cancer has yet been cured by suchmeans. The outstanding success in palliation sofar achieved by chemotherapy has been the use ofoestrogens in the treatment of cancer of the prostate.

It is customary to regard cancer as a hopelessdisease and for references to appear frequently tothe search for a "cure," as though no method ofcuring any form of this condition was known, andas though it was a single disease entity requiringonly some one magic drug for its elimination.This hopeless attitude towards what has beenachieved and faith in some single "cure" thatawaits us round the corner is by no means confinedto the lay public and is responsible for some of thedelay that occurs in sending patients for treatmentat an early stage of the disease while it is stillcurable by means already at our disposal. Cancerat most sites in the body is curable if treated early.Even more is to be expected from improved methodsof early diagnosis and the recognition by themedical profession as a whole of the urgency ofsending a patient with cancer to a centre wherefull modern facilities for treatment are available,than from the improvements that are taking placein the existing treatment methods. While newdiscoveries related to the various predisposingcauses of cancer at different sites in the body, andthe cause might well revolutionise treatment ofmalignancy within the cell, such advances may, forall we know, be long delayed. In the meantime,while we wait for practical results to appear fromthe careful and patient research work that is beingcarried out, over 70,000 persons die from cancer inthis country each year, many of them quite un-necessarily, because the available treatment thatcould have cured them at one stage was eitherapplied too late or not applied at all.A woman with a lump in the breast requires

investigation to exclude cancer, and treatment forcancer if the diagnosis is established, as urgentlyas a patient with acute appendicitis or a per-forated gastric ulcer requires operation. To taketwo extreme examples: (i) Patients who workwith pitch and tar are liable to skin cancer but therisk is appreciated, they are examined at regularintervals by their industrial medical officers andtrained to report the smallest skin lesions. The



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142 POST-GRADUATE MEDICAL JOURNAL May, I946symptom-free rate in this group of patients withadequate treatment is I00 per cent. (2) Cancerof the lung on the other hand has an insidiousonset starting as a rule with a dry cough, oftenof a different character to any cough that thepatient may have had previously, but causinghim no alarm at first so that he seldom reports itto his doctor until he either develops pain, feelsweak and tired, or has an haemoptysis. If hedoes report early he is often reassured and givena bottle of medicine. Even if X-rayed in theearly stages he is all too frequently merely toldto come back in a month or two for a repeatexanmnation either because the shadow was notlarge enough to leave no doubt as to its natureradiologically or because the radiograph showedno abnormality. By the time that a bronchoscopyis first performed the great majority are inoperableand most of the remainder beyond the stage whenradiotherapy can achieve more than temporarypalliation. In a recent review of I50 consecutivenew cases of cancer of the lung seen in one year atthe joint consultation clinic held by members ofthe staffs of the Brompton Hospital for Diseasesof the Chest and the Royal Cancer Hospital it wasfound that the average delay in reporting the firstsymptom to a doctor was 3 5 months, and theaverage delay from this first consultation till thepatient came for treatment was a further 5 months:8 * 5 months average delay, the greater part ofwhich was directly or indirectly the responsibilityof the medical profession.

Surgery and radiotherapy are partners in thetreatment of cancer; in some cases either alonewill produce comparable results, in others one issuperior, and in a third group the patient's bestprospect lies in a planned combination of the two.We are here concerned with the r6le of radio-therapy but it is wrong to regard this method oftreatment in isolation. Radiotherapy is now wellestablished, its field is becoming better definedand is expanding as knowledge and improvedtechnical facilities increase. Advances in accuracyof application have removed most of its dangersin experienced hands and further improvement inresults is confidently to be expected.

Radiotherapy for Accessible CancerThe outstanding achievements of radiotherapy

have been in the treatment of accessible cancer.It plays the paramount part in the treatment ofcancer of the skin. A symptom-free rate of overgo per cent is obtained with adequate treatmentfor basal-cell carcinomata and with the help ofsurgery in the more resistant cases a disease-freerate of Ioo per cent should be obtained. Withsquamous-cell carcinoma of the skin the positionis complicated by the liability to metastases, but

the local primary tumour should be eradicated innearly every case and in combination with surgerya 70-80 per cent symptom-free rate can be achievedeven with the present far too high proportion oflate cases that are coming to hospital.

Cancer of the lip and mouth are now pre-dominantly the province of the radiotherapist.A judicious selection of treatment method, frominterstitial radium implants and contact X-raytherapy for the primary sometimes combined withblock dissection of the neck, to X-rays and tele-radium for both the primary and the neck nodesin the later cases, produces. a five-year survival-rate of approximately 65 per cent in early casesand one of over 30 per cent in all cases treated.Such results are, however, only obtained at someof the larger centres, notably at the ChristieHospital and Holt Radium Institute in Manchester.

Intrinsic carcinoma of the larynx is being treatedby radiotherapy with increasing frequency and isdisplacing surgery, despite the fact that brilliantsuccesses have been achieved by this means,largely because the results of radiotherapy arecomparable with those of surgery in the earliercases, are superior in the later ones and the mutila-tion of total laryngectomy is avoided. ContactX-ray therapy after removal of part of the thyroidcartilage (a good example of the increasing use ofsurgery to give access for radiotherapy) is employed,but the majority of these cases are now treated byX-rays applied externally or by teleradium whichseems to have several advantages in this situation.Lederman has recently published an account of23 operable cases of intrinsic cancer of the larynxtreated by teleradium at the Royal Cancer Hospitalin which i8 were alive one year after treatment,and 5 of which had lived 5 years or more. Othermalignant tumours of the pharynx and larynx arealmost exclusively treated by external irradiationwith variable success but with definite improve-ment over the past ten years.

Cancer of the breast is now recognised as beingthe joint concern of both surgeons and radio-therapists neither alone being able to achieveresults comparable with those resulting fromcombined treatment. McWVhirter at the RoyalInfirmary, Edinburgh has shown that the symptom-free rate in cases with no evidence of lymphnodeinvolvement can be raised to go per cent by com-bined treatment, and that where lymphnodes areinvolved the symptom-free rate can be more thandoubled if X-ray treatment is added to surgery; a50 per cent symptom-free rate being obtained inthose operable cases which are found to havemetastasised to lymphnodes.

Miss Hurdon will be long remembered Jor herwork in the radium treatment of cancer of thecervix uteri at the Marie Curie Hospital where a



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Mav. i'46 RADIOTHERAPY AND CANCER 143

five-year survival-rate of 8o per cent was obtainedin Stage I cases and of 35 per cent in all cases seen.Radium applied to the uterus and vagina combinedwith external high voltage X-rays based both onscientific principles of distribution of the energy-absorbed and on the biological response of indi-vidual tumours as recorded, for instance, by Spearand Gliicksmann at the Strangeways Laboratory inCambridge should improve these results still further.

Radiotherapy for Deep-Seated CancerWith deep-seated cancer the results of radio-

therapy are still far from satisfactory but notableadvances have been made in recent years. Thetechnical problems of administration of adequatetreatment are greatly increased when the tumouris situated at a depth, but there is evidence thatthese can now be overcome to a great extent.

Cancer of the oesophagus is still rarely cured byany means, though Guisez in Paris obtained somegood results with a radium bougie. An account ofthree five-year survivals following external high-voltage X-ray therapy has been published fromthe Royal Cancer Hospital. Cancer of the stomachand intestine is almost the exclusive province ofthe surgeon. Surgery has many cures of cancerof the rectum to its credit, a number of thesepatients being alive and well 2o years or moreafter treatment. The use of very high voltageshas already brought about an improvement in theX-ray treatment of the more advanced cases ofcancer of the rectum, the work of Phillips with themillion-volt X-ray therapy plant at St. Bartholo-mew's Hospital being outstanding in this field.

In the urogenital tract surgery is the method ofchoice in most cases though the improvement inthe treatment of cancer of the bladder by means ofradon seed implants or external high-voltageX-rays is giving radiotherapy a prominent placein the treatment of tumours at this site.

Cancer of the lung presents an exceptionallyinteresting problem both on account of the apparentincrease in frequency of this disease and theexcellent results obtained in a few cases by pneu-monectomy. The number of patients suitable forthis operation is, however, so small that a concen-trated attack upon this disease by means of X-raysis being undertaken. Little success was achievedwith the old methods but an improved method ofX-ray treatment adopted over the past two yearsat the Royal Cancer Hospital has shown thatextremely valuable palliation can be achievedand that a number of patients can be returned towork free from symptoms. It will be of greatinterest to see if this freedom from symptoms willbe maintained in a reasonable proportion of thecases so treated.The connective tissue sarcomata have been

regarded in the past as radioresistant but thisconclusion was reached mainly on a basis of theimmediate clinical response, and further work isrequired before they are lightly dismissed as beyondthe scope of radiotherapy. There are those whomaintain that a combination of irradiation andremoval of the limb or tissues affected offers thebest prospect of success. It is to be hoped that agroup of workers will combine to investigate theresponse of these tumours to the various com-binations of treatment method at present avail-able, as there is some evidence that more couldbe done for these patients than is being achievedat present. Too few cases are seen in any onecentre for a planned research programme to becarried out in a reasonable time.The lymphadenopathies and leukaemias are

treated by radiotherapy and useful palliationusually obtained, though no real progress towardscuring these diseases has yet been made. Thiswould seem to be one of the fields where the useof radiotherapy as a means of relieving symptomsand improving the patient's general condition maywell be combined in the future with attempts at amore fundamental attack upon the disease processby means of chemotherapy or hyperpyrexia. Theintriguing prospect of the introduction of arti-ficially radioactive elements into compounds withknown growth inhibitory action is one which mightpossibly link chemotherapy and radiotherapytogether in an attempt to deal with this group offatal diseases.

There are a number of other sites where radio-therapy has a part to play in the treatment ofmalignant disease, such as the thyroid, brain,and salivary glands, for instance, but no morethan an indication of the scope of radiotherapy canbe given here. As a means of palliation inadvanced cancer and particularly in the relief ofpain, radiotherapy is the most valuable therapeuticmethod at our disposal. Its place in cancertreatment would be assured on these grounds aloneeven if it were not successful in curing a singlepatient with this disease. Advances in apparatusconstruction and the availability of artificial radio-active substances, together with increasing know-ledge of the response of individual tumours andthe tissues around them to irradiation holds outexciting prospects for the radiotherapist. Theradiotherapist would, however, gladly postpone theacquisition of these long awaited additions to hisdepartment in exchange for a few months off theaverage length of history given by the patientswith cancer who come for treatment. He wouldimprove his results more by decreasing the intervalbetween patients' first visits to their doctors andtheir first treatment than by adding any costlynew piece of apparatus to his existing equipment.



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SummaryRadiotherapy is the use of some ionising radia-

tions in medicine to produce a biological effect,either in the form of particles or waves of sufficientenergy to produce the effect desired. Theseradiations are obtained from radioactive elementsundergoing spontaneous disintegration (e.g. radiumor radon); from elements previously excited which,when reverting to their normal state, give off theenergy acquired (e.g. radioactive phosphorus, orstrontium) from X-ray tubes where metals (e.g.tungsten) are bombarded with electrons; or fromapparatus either designed to accelerate heavyparticles and produce a beam of neutrons(Cyclotron) or to accelerate electrons, which maybe used directly, but more probably to producevery high-voltage X-rays (Betatron). The absorp-tion of energy from these radiations results inintense electronic activity in the tissues.The amount of damage done depends on the

amount and distribution of the energy absorbed,the rate of absorption, the intervals betweenexposures, the total treatment period, the sensi-tivity of the cells, and the nature and state of thetumour bed. A wide variety of apparatus isnecessary for the efficient treatment of all types ofcase. The results of treatment with early acces-sible cancer are excellent and with deep-seatedcancer are improving, and may be expected toimprove considerably in the future. Earlierdiagnosis and treatment and more knowledge of thebiological effects are now more urgently neededthan technical advances on existing lines.

AcknowledgementThis paper is based on a short series of lectures

given to medical students at the Royal FreeHospital. I am indebted to Dr. P. C. Koller andto Mr. L. F. Lamerton for the helpful advice theygave me in their preparation.

THE TREATMENT OF SUPPURATIVE OTITIS MEDIA*By S. E. BIRDSALL, F.R.C.S.

My subject deals with suppurative otitis media,acute or chronic, and from the clinical aspect itcomprises the majority of patients who presentthemselves to the practitioner with dischargingears.

It is the practitioner's first duty to decidewhether the discharge is from the external meatusor from the middle-ear, and it is obvious that notreatment can logically be prescribed until thisdistinct point has been settled.

It is an unfortunate fact that the presentmedical curriculum provides inadequate instruc-tion in many so-called special subjects. Anygeneral practitioner is certain to meet in hispractice with many patients suffering from otor-rhoea in the course of a year, and they willcertainly be greater in number than those whomhe finds with appendicitis or carcinoma of thealimentary canal, yet in his studentship he willhave gained very scanty knowledge of the commoncondition of otitis media, compared with hisintimate knowledge of the far rarer abdominaldiseases.

Confronted with a patient who has a dischargingear, it is essential to know the origin of the dis-charge; is the diagnosis one of otitis externa or ofotitis media? The distinction may be difficult.The following points may be helpful.

* Based on a lecture at The Memorial Hospital, S.E.i8,on 9.3-46.

First.-In otitis externa, tenderness is marked,and pain may be slight. In otitis media, pain maybe very severe, and tenderness of the pinna isinvariably absent. Mastoid tenderness may bepresent in either condition.

Secondly.-The character of the discharge affordsvaluable evidence. In amount, it is more copiousin otitis media. All discharge must first be re-moved by mopping or syringing. If it rapidlyreappears, then we are probably dealing withotitis media, in which the secretion in the meatus isthe overflow from an infected cavity lined withmucous membrane. In otitis externa, the secre-tion is derived from the skin lining the meatus,and it will not be replaced in a shorter time thanan hour. If the discharge contains mucus, thenit must come from the middle-ear as there are nomucous glands in any skin. The discharge inotitis externa is often bright yellow, as thoughstained with flavine.

Thirdly.-The meatus is usually healthy inotitis media. In otitis externa there is usuallysome stenosis and the meatus may be very narrowowing to swelling of the lining skin, which eitheritches or is acutely tender.

Fourthly.-In a disease affecting the ear, noexamination is complete unless the hearing betested. It is essential first to clean the meatusof discharge. In otitis externa the hearing willbe normal or but slightly diminished. In otitis



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radiotherapy cancer - postgraduate medical journal · (i) the physical basis of radiotherapy...

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