Prospects in Radiosurgery
2
1373 LEADING ARTICLES Prospects in Radiosurgery THE LANCET LONDON 26 JUNE 1965 HOPES were reasonably high that research into the physics of high-energy atomic particles, using the mas- sive and expensive accelerating machinery throughout the world, would eventually help the practice of medi- cine and particularly radiotherapy. Deeply penetrating beams of the atomic nuclei of hydrogen (protons) and helium (alpha particles) and the biologically highly active neutrons were envisaged as more effective and more precise beams in radiotherapy and as knife-like rays in surgery. Trials began in 1935 when the LAw- RENCE brothers used protons and neutrons from their 60-inch cyclotron in animal experiments, and four years later, with R. S. STONE,2 they applied the method in human radiotherapy. These workers were far ahead of their time, however, and enormous difficulties of dose measurement and dose fractionation effects halted their bold clinical trials.3 They went on to found, in the University of California, at Berkeley, the Lawrence Radiation and Donner Radiobiological Laboratories, now of great international importance. Physicists everywhere have since made vast progress in under- standing and controlling these particles. But their difficulties have been light compared with those that are still being encountered in attempts to apply this new physics to biology and medicine. Advances in the con- ventional techniques of radiotherapy have meanwhile made available more energetic X and gamma rays for deep penetration, soft electron beams for very low penetration, and reliable techniques for implanting radioactive gold or yttrium for precisely localised effects. It is against this wide versatility that beams of high- energy atomic particle must compete in usefulness. One advantage which charged-particle beams would have, it was hoped, was the Bragg peak effect.4 5 Pro- tons and alpha particles will travel so far through tissue -the distance depending upon their energy-and then stop. The amount of energy per unit of track length that they deposit in the tissue increases to two or three fold in the last millimetre of their path where ionisations become more frequent. This " peaking " of the dose enhances the ratio of the target dose to the entrance dose at the skin-and there is no exit dose. It is known too,l 6 that at the end of their range in the Bragg peak region, where the particles are slowing down, the form of the energy deposited is more biologically effective than at the point of entry where they are travelling faster. 1. Lawrence, J. H., Lawrence, E. O. Proc. natn. Acad. Sci U.S.A. 1936, 22, 124. 2. Stone, R. S., Lawrence, J. H., Archibald, P. C. Radiology, 1940, 35, 322. 3. Stone, R. S. Am. J. Roentg. 1948, 59, 771. 4. Bragg, W. H., Kleeman, R. D. Phil. Mag. 1904, 8, 726. 5. Wilson, R. R. Radiology, 1946, 49, 487. 6. Zirkle, R. E. Am. J. Cancer, 1935, 23, 558. At the target this increase in effectiveness is due to an increase in the density of ionisations, and it produces biological changes which are less affected by anoxia. Anoxia always tends to protect cells from less densely ionising X and gamma rays, and is thought thereby to play a significant part in the resistance of many tumour cells to damage by X and gamma rays. With all these apparent advantages of the Bragg peak, it seems disappointing that, whenever attempts are made to construct suitable dose distributions to fit a clinical situation, the superiority of Bragg-peak radiation over conventional radiotherapy is difficult, if not impossible, to sustain. The trouble with the Bragg-peak method is that, although beams of fast particles scatter very little, when the particles are slowed down by energy atten- uators for focusing and by tissue on the way to the target, they do begin to scatter. The beam profile at the end of the track is then less sharp, and this poor geometry makes the sharp focusing of the peak on to a small target almost impossible. With broader beams for larger targets the Bragg peak, being confined to the last millimetre or two of the beam track, fails to confer its advantages over most of the volume of a large tumour. If this drawback is, in turn, overcome by graded wedges in the beam path to " scan " the Bragg peak through the tumour volume, then any peaking effect of dose at the end of the beam is almost completely lost.’ 7 In the radiosurgery of the normal pituitary gland, these difficulties have made it impossible to eliminate pituitary function completely with Bragg-peak irradia- tion without at the same time seriously endangering the structures surrounding the sella. 8 Similarly, attempts to focus the Bragg peak of small beams on the ventro- lateral nucleus of the thalamus in the radiosurgery of Parkinson’s disease would be in difficulty because of the necessarily high dose to the surrounding diencephalon. Broader beams of particles for stereotactic Bragg-peak therapy of cerebral tumours would be unlikely com- petitors with the more versatile methods of conventional X and gamma rays. LAWRENCE and his colleagues in Berkeley have used a radiation beam of particles passing right through the target, and they concentrated the dose within the target by accurately rotating the patient. 8 Their 910 MeV alpha-particle beam of 7 mm. diameter retains a sharp profile throughout the necessary distance from the skin to the target, and the Bragg peak then falls into space well beyond the patient and is ignored. Excellent results are forthcoming from their irradiation treatment of moderate-sized intra-sella pituitary tumours pro- ducing acromegaly or Cushing’s syndrome 9 10 where the tumour dose required is about 8000 rads. But, in the management of diabetic retinopathy or disseminated carcinoma of the breast, attempts to destroy totally the apparently normal pituitary gland with much higher doses of radiation have been curtailed, again 7. Larsson, B. Br. J. Radiol. 1961, 34, 143. 8. Tobias, C. A., Roberts, J. E., Lawrence, J. H., Low Beer, B. V. A., Anger, H. O., Born, J. L., McCombs, R., Huggins, C. University of California Radiation Laboratory (UCRL), 1955, report no. 3035. 9. Lawrence, J. H., Tobias, C. A., Born, J. L., Sangalli, F., Carlson, R. A. Linfoot, J. A. Acta radial. 1962, 58, 337. 10. Lawrence, J. H., Tobias, C. A., Born, J. L., Gottschalk, A., Linfoot, J. A., Kling, R. P. J. Am. med. Ass. 1963, 186, 236.
Transcript of Prospects in Radiosurgery
1373LEADING ARTICLES
Prospects in Radiosurgery
THE LANCETLONDON 26 JUNE 1965
HOPES were reasonably high that research into thephysics of high-energy atomic particles, using the mas-sive and expensive accelerating machinery throughoutthe world, would eventually help the practice of medi-cine and particularly radiotherapy. Deeply penetratingbeams of the atomic nuclei of hydrogen (protons) andhelium (alpha particles) and the biologically highlyactive neutrons were envisaged as more effective andmore precise beams in radiotherapy and as knife-likerays in surgery. Trials began in 1935 when the LAw-RENCE brothers used protons and neutrons from their60-inch cyclotron in animal experiments, and four
years later, with R. S. STONE,2 they applied the methodin human radiotherapy. These workers were far aheadof their time, however, and enormous difficulties ofdose measurement and dose fractionation effects haltedtheir bold clinical trials.3 They went on to found, inthe University of California, at Berkeley, the LawrenceRadiation and Donner Radiobiological Laboratories,now of great international importance. Physicistseverywhere have since made vast progress in under-standing and controlling these particles. But theirdifficulties have been light compared with those that arestill being encountered in attempts to apply this newphysics to biology and medicine. Advances in the con-ventional techniques of radiotherapy have meanwhilemade available more energetic X and gamma rays fordeep penetration, soft electron beams for very low
penetration, and reliable techniques for implantingradioactive gold or yttrium for precisely localised effects.It is against this wide versatility that beams of high-energy atomic particle must compete in usefulness.One advantage which charged-particle beams would
have, it was hoped, was the Bragg peak effect.4 5 Pro-tons and alpha particles will travel so far through tissue-the distance depending upon their energy-and thenstop. The amount of energy per unit of track lengththat they deposit in the tissue increases to two or threefold in the last millimetre of their path where ionisationsbecome more frequent. This " peaking " of the doseenhances the ratio of the target dose to the entrancedose at the skin-and there is no exit dose. It is known
too,l 6 that at the end of their range in the Bragg peakregion, where the particles are slowing down, the formof the energy deposited is more biologically effectivethan at the point of entry where they are travelling faster.1. Lawrence, J. H., Lawrence, E. O. Proc. natn. Acad. Sci U.S.A. 1936,
22, 124.2. Stone, R. S., Lawrence, J. H., Archibald, P. C. Radiology, 1940, 35, 322.3. Stone, R. S. Am. J. Roentg. 1948, 59, 771.4. Bragg, W. H., Kleeman, R. D. Phil. Mag. 1904, 8, 726.5. Wilson, R. R. Radiology, 1946, 49, 487.6. Zirkle, R. E. Am. J. Cancer, 1935, 23, 558.
At the target this increase in effectiveness is due to anincrease in the density of ionisations, and it producesbiological changes which are less affected by anoxia.Anoxia always tends to protect cells from less denselyionising X and gamma rays, and is thought thereby toplay a significant part in the resistance of many tumourcells to damage by X and gamma rays. With all theseapparent advantages of the Bragg peak, it seems
disappointing that, whenever attempts are made to
construct suitable dose distributions to fit a clinical
situation, the superiority of Bragg-peak radiation overconventional radiotherapy is difficult, if not impossible,to sustain. The trouble with the Bragg-peak method isthat, although beams of fast particles scatter very little,when the particles are slowed down by energy atten-uators for focusing and by tissue on the way to thetarget, they do begin to scatter. The beam profile atthe end of the track is then less sharp, and this poorgeometry makes the sharp focusing of the peak on to asmall target almost impossible. With broader beamsfor larger targets the Bragg peak, being confined to thelast millimetre or two of the beam track, fails to conferits advantages over most of the volume of a large tumour.If this drawback is, in turn, overcome by gradedwedges in the beam path to " scan " the Bragg peakthrough the tumour volume, then any peaking effect ofdose at the end of the beam is almost completely lost.’ 7In the radiosurgery of the normal pituitary gland,these difficulties have made it impossible to eliminatepituitary function completely with Bragg-peak irradia-tion without at the same time seriously endangering thestructures surrounding the sella. 8 Similarly, attemptsto focus the Bragg peak of small beams on the ventro-lateral nucleus of the thalamus in the radiosurgery ofParkinson’s disease would be in difficulty because of thenecessarily high dose to the surrounding diencephalon.Broader beams of particles for stereotactic Bragg-peaktherapy of cerebral tumours would be unlikely com-petitors with the more versatile methods of conventionalX and gamma rays.LAWRENCE and his colleagues in Berkeley have used
a radiation beam of particles passing right through thetarget, and they concentrated the dose within the targetby accurately rotating the patient. 8 Their 910 MeV
alpha-particle beam of 7 mm. diameter retains a sharpprofile throughout the necessary distance from the skinto the target, and the Bragg peak then falls into spacewell beyond the patient and is ignored. Excellentresults are forthcoming from their irradiation treatmentof moderate-sized intra-sella pituitary tumours pro-ducing acromegaly or Cushing’s syndrome 9 10 wherethe tumour dose required is about 8000 rads. But, in themanagement of diabetic retinopathy or disseminatedcarcinoma of the breast, attempts to destroy totallythe apparently normal pituitary gland with much
higher doses of radiation have been curtailed, again7. Larsson, B. Br. J. Radiol. 1961, 34, 143.8. Tobias, C. A., Roberts, J. E., Lawrence, J. H., Low Beer, B. V. A.,
Anger, H. O., Born, J. L., McCombs, R., Huggins, C. University ofCalifornia Radiation Laboratory (UCRL), 1955, report no. 3035.
9. Lawrence, J. H., Tobias, C. A., Born, J. L., Sangalli, F., Carlson, R. A.Linfoot, J. A. Acta radial. 1962, 58, 337.
10. Lawrence, J. H., Tobias, C. A., Born, J. L., Gottschalk, A., Linfoot,J. A., Kling, R. P. J. Am. med. Ass. 1963, 186, 236.
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because of the danger to surrounding structures.l1 Forthe destruction of the normal pituitary in diabetes andbreast cancer it seems that yttrium-90 or gold-198implantation into the gland through the nose is moreeffective, and may become the most reliable and safesttreatment. 12 13 Many workers throughout the world,however, still advocate for these conditions surgicalhypophysectomy by an intracranial or trans-sphenoidalapproach. There is no doubt that for larger pituitarytumours, especially those extending outside the sella,compressing the hypothalamus, and producing, amongother effects, hypopituitarism and visual-field defects,some help is to be gained from conventional radiationtherapy,14 but the main management must be thetask of the neurosurgeon.12 LAWRENCE is also trying totreat Parkinson’s disease by producing radiation lesionsof approximately 0-1 ml. in the thalamus. When theradiation lesion increases very slightly in size with time(the effects of the lower doses of radiation which
immediately surround the main lesion are often delayedfor four or more years) then this increment might keeppace with the progress of the disease and continue to
keep its symptoms at bay. LEKSELL et al.15 in Sweden
had, in early pioneer work, been enthusiastic about theuse of the proton beam for the radiosurgery of mid-brain tractotomies for pain, leucotomy for psychoses,and thalamotomy for Parkinson’s disease; but they nowfavour a trial using multiple well-collimated beams ofcobalt-60 gamma rays simultaneously focused on thetarget in the brain.
All would agree that conventional neurosurgery isnot so advanced that it can afford to be complacentabout the safety of its standard methods, and these con-tinuing efforts by neurosurgeons and endocrinologiststo
"
operate " inside the head without having to open
must be encouraged. Unfortunately, the hopes for pro-cedures of wider scope mentioned at the Second Inter-national Congress of Neurological Surgery 16 in 1961are no nearer realisation. In the management of malig-nant tumours, therefore, it seems improbable that muchfuture radiation therapy will come from the acceleratorsof heavy charged particles. Neutrons, however, are
particles carrying no charge and in no need of massivemachinery for their acceleration. Neutron beams haveno Bragg peak and their intensity " decays " like X andgamma rays. They do nevertheless have many advan-tages in irradiation therapy by virtue of the density ofthe ionisation they produce, 1 7 18 and they can now beaccelerated relatively cheaply.xg 2o High-intensitysources of fast neutrons are being developed for radio-therapy, and it is hoped that LAWRENCE’S earlier clinicaltrials of neutron therapy will be repeated.2o11. Lawrence, J. H., Tobias, C. A., Linfoot, J. A., Born, J. L., Gottschalk,
A., Kling, R. P. Diabetes, 1963, 12, 490.12. Falconer, M. A. Proc. R. Soc. Med. 1965, 58, 62.13. Fraser, R., Joplin, G. F., Hartog, M. Paper read at the Royal Society
of Medicine, March 25, 1964.14. Poppen, J. L. Bull. N. Y. Acad. Med. 1963, 39, 21.15. Larsson, B., Leksell, L., Rexed, B. Acta chir. scand. 1963, 125, 1.16. Lancet, 1961, ii, 1137.17. Gray, L. H., Conger, A. D., Ebert, M., Hornsby, S., Scott, O. C. A.
Br. J. Radiol. 1953, 26, 683.18. Fowler, J. F., Morgan, R. L. ibid. 1962, 35, 577.19. Lomer, P. D., Greene, D. Nature, Lond. 1963, 198, 200.20. Fowler, J. F., Morgan, R. L., Wood, C. A. P., and others. Br. J. Radiol.
1963, 36, 77 et Seq.
But the research on heavy charged particles continues,and a beam of negative pions-particles predicted tohave great potential for radiation therapy 21-is beingcarefully examined for therapeutic applications. Inaddition to producing straight beams, the big accelera-tors supply an increasing number of new isotopeswhich, together with new radiation camera techniques,provide opportunities for the expanding science of nuc-lear medicine. And lastly, the projected omnetron, amachine proposed in Berkeley to accelerate all ions
(even uranium ions) to the massive energy levels of500 MeV per nucleon, and thus produce densities ofionisation that will eliminate all anoxic protectionand recovery of cells, will be the latest tool in this
sledgehammer approach to the radiation therapy ofcancer.
AmphetamineTHE Brain Committee22 found that during 1959 over
51/2 million prescriptions (21/2%) were for amphetamineor phenmetrazine; and a Ministry of Health study23 ofprescribing habits in general practice during 1961 and1962 showed that stimulants of the amphetamine typewere given to patients three to five times more often thanwere other antidepressants. Even allowing for use as anappetite suppressant, this probably indicates a preferenceamongst general practitioners for amphetamine in themanagement of mental ill-health which hospital psychia-trists find it hard to understand-or condone. Whatthen are the reasons for its use, the alternatives, and therisks involved ? The contrasting views of psychiatristsand general practitioners may be partly a reflection ofthe different people they treat. In a study of eightypractices in London, SHEPHERD et al. 24
" confirmed theexistence of vulnerable sub-groups suffering from minordisorders which are inadequately represented in hos-pital practice ": neurotic illness is plainly an importantcause of chronic ill health in general practice. These
time-consuming patients, perhaps having been treatedunsuccessfully as hospital outpatients, sometimes findthat amphetamine prescribed by their general practitionergives them the energy or enthusiasm to overcome theirpersonal or environmental difficulties. Many take thedrug intermittently or in low dosage at times of crisis,and they differ strikingly from the younger disruptivepsychopath who is seen in hospital practice and whotakes increasing numbers of tablets to regain a waningeuphoriant effect as tolerance develops.The Ministry of Health survey 23 also showed that
two-thirds of all prescriptions were for drugs introducedbefore 1956. In the treatment of some conditions this is
commendably conservative; but it is also true that untilthe advent of other drugs afrer 1956 amphetamine wasthe only alternative to electroconvulsive therapy or hos-pital admission in the treatment of depressive illness. At21. Fowler, P. H., Perkins, D. H. Nature, Lond. 1961, 189, 524.22. Ministry of Health and Department of Health for Scotland. Drug
Addiction. Report of the Interdepartmental Committee. London, 1961.23. Rep. publ. Hlth med. Subj., Lond., 1964, 110.24. Shepherd, M., Cooper, B., Brown, A. C., Kalton, G. W. Br. med. J.
1964, ii, 1359.
