1. health and fitness
2. disease
3. cancer

MAY 9,
19141,
THE CAUSEI AND CTURE OF CANCER.
A
Jtednlrr
ON
THE" C.AYSE AND C'I OTI CANCER VIEWAED
IN THE LIGHT OF RECENT, RADIOBIOLOGICAL RESEARCH.;
DELIS ERED BEFORE THE MEDICAL FACULTY OF THE
-UNIVERSITY
OF LEEDS.
By W. S. LAZARUS-BARLOW, M.D.,
F.R.C.P.,
DIRECTOR OF THE CANCER RESEARCH LABORATORIES, THE MIDDLESEX
HOSPITAL; LECTURER ON GENEItA, PATHOLOGY IN THE
MEDICAL SCHOOL.
[AFTEr. acknowledging thle lhonour
done
hlim
by the
university in asking him to deliver a special lecture upon
a stubject of so much -importance as cancer, the lecturer
continued as below.]
The fact that tlle comprellensive title of " cancer
problems" was specifically given me by the Dean of the
Medical Faculty I regarded as an instruction to treat
what I wislhed to say in a broad and bold manner. I felt
tllat clearness of outline was desired, and that a meticulous attention to detail witlhin the limits of an hour's
lecture was neitlher possible nor advantageous, unless the
"problems" I was to discuss were of a kind that might
not greatly interest my audience. Hence I determined,
not without trepidation, to take my courage in both
hands, and attempt to address you on the two fundamental
problems of cancer-its cause and its cure-in the light of
that experimental work with which I am most conversant.
In imy Croonian Lectures before the Royal College of
Pllysicians (1909)1 I foreshadowed some such suggestions as I am about'to make to-day, but five years' additional work lhas shown me that wlhereas some of my data
were capable of bearing the interpretation I put upon
them others were not. In particular I am now satisfied
tllat the property of affecting a photographic plate in the
dar:k evinced Jby so .many aniimal (and other) substances
(a property specifically termed " skotographic " in view of
tlle uncertainty of its nature) is not evidelnce of radioactivity butt depends in large part, if not altogether, upon
the formation of 'minute traces of aiimmonia. Butt though
tllis which was thlouglht possible evidence of radio-activity
is now known to be valueless in* this direction, other
points lhave been brought to light which link radio-activity
and cancer more closely than was thouglit possible five
years ago.
RADIO-BIOLOGICAL RESEARCH
AND THE CAUSE OF
CANCER.
At the very outset of this my first "cancer problem " I
lhave to beg you to remember that it is generally held that
cancer is not a single disease. We are told that we have
only to think of the very different histological and clinical
pictures presented by a scirrhus of the breast, a periosteal
sarconma, an endosteal or myeloid sarcoma, a rodent cancer,
to be iv ware of this fact. And proceeding logically, we
are told that if many diseases be included under the
name "cancer" it is legitimate to hold the view that
many different causes are responsible for its manifestation. This has been the position taken by the profession until thel"causes of cancer" have multiplied to
such an extent that at the present day the sole
"cause" to which universal assent is given is "chronic
irritation."
Now, whlile I am 'not in a position to deny that different
diseases are included under the one name, btut "on the
contrary, as will be seen later, shall mnaintain that tbere-is
a specificity far greater than lhas been imagined hitherto,
and while I feel that thie great group of carcinomata
divides itself naturally from the great group of the
sarcomata, and both of these from the non-malignant neoplasms, yet I would ask you to remember that the growtll
of all the different systems whicll go to make5up the
animal body is initiated by the coalescence of a single
spermatozoon witlh a single ovum. If one probe deeplv
enoughl all varieties of abnormal growthl nmust depend
upon local abnormal stimulation of a cell capable of
r
Tuxz BRImsu
MEDICAL JOURNAL
1001
division, and in the case of cancer it may well be that one,
or at most few, fundamental factors-underlie the whole
cumbrous superstructure of chronic irritation. Withotit
removing. the etiology of cancer from the subject of
upsolved problems, I wvould suggest that in radiations, and
particularly-in--radium. raliations, we lhave an agencywlhiclh nlight well serve as a cause of cancer to tile
exclusion of all otiers.
; mnaking tllis suggestion are as follows:
!N "gounids for
1. Radium is wvidely distribitted througyhout ntatute inz
such qutantittes' as hbave been sh1owv capcable of izdducing
accelerated diVision of cells.
The richest ore -.St. Joacllimstlial pitchlblende --contains a maximum of about 0.0003 ma. radium element
per gram (3 x 10--4 mg.), but this quantity is relatively
enormous, the greater number of rocks containing radiuLn
in amounts of the order 10--9 mg. per gram. Now,
one thousand millionth of a milligranm is the limit of
detectability of radium, but quantities above one fivehundred milliontll (2xl0
x
9 mg.) sff a milligram. can be
measured, with about 10 per cent. error, by means of
the emanation electroscope. Hence, in spite of the
apparently ridiculous insignificance of tlle quantities of
wlliclh I am about to speak, it is certain that tlley are
approximately correct.
In a reseaarch involving the separate counting of
half a million ova of Ascaris megalocephala Becktoil
and I 2 found that if radium act on the ova in tlle
resting stage in quantities of the order 5X10--7 mg., and
for a continuous period of about thirty hours at 0° C., on
subsequent inctubation at 37° C. cellular division proceeds
at an accelerated rate. These effects are brought about
by the action of alpha, beta, and gamma rays acting
togetlher; they can, Ilowever, be induced by beta and
gamma rays alone-alpha rays being excluded-if tlho
amouLnt of radium be about one hundred timnes as great
(5 x 10 i lg.).
This evidence of stimulation by radium does not stand
alone. Quite apart from the fact that there is a considerable amount of clinical evidence to show that uleo
plasms treated with radium, mesothorium, or x ra-liation may manifest a verv definite increase in rate of
growthi which synchronizes closely with the initiation
of treatmlent witli rays, and quite apart from the fact
that every hiistological examination of a neoplasm which
lhas undergone retroaression as tlie result of radium or
x radiation siows a remarkable increase in the number of
connective tissue cells, there is very definite evidence of
growth stimiulation 'by, -irays in the vegetable kingdom
(Cattley, 3 Molisch, 4 Stoklasa and Zdobnicky 5). Of a
similar kind are mi-y experiments with Dunbar B upon tlle
muscle-nerve preparation of the frog, wlherein I showed
that a muscle nerve exposed to the alpha, beta,
and gamma rays of 7 mg. of RaBr2 lives longer and coIltracts under smaller stimulation tlhan its non-irradiatecl
fellow. Stimulation under x rays is also shown by the
experiments of Beckton, Hastings, and Wedd7 upon
silkworms.
If the various experiments and conditions under wlliclh
stimulation lias been observed be compared in respect of
the amounits of radiation -necessary to evoke an increased
rate of growth, it will be seen that, though the amounts
are small, yet they actaally differ within wide- limits.
We have here one example of that selectivity in- aetioii
of rays to which I shall refer more fully, later. -It will
suffice lere to recognize that a wide variety of cells
lhas b6en demonstrated to be capable of nillha,nced rate
of growth under irradiation, provided tthat:V the* dose
bf irradiation be suitable for the type of cells unde
experiment.
2. Bacteria suslpended in a radium'l-containing
collect the radiou m from that fluid.
flutid
Wlietller by imnbibition, adsorption, or tlie formatUoin of
g chemical (albuminousy compouind, bacterias.4spended
in a solution containing radium acquire a greater radium
percentage than tile supernatant fluid, and even a gi ea'er
percentage
than;the original fluid.
The following figures were obtained in experiments
I mnade8witli living and dead Staph7ylococcus aureuts, and
with mixedaerial bacteria, the former at 370 C., the latter
at room temperature. The original brotlh contained
- -.%
-
[27843
BRITteH
THI 'E CAUSE AND CURE OF CANCER.
rHF.
I
1002IOIRDICAL
JOURN-AL J
1.74 x 105 mg. Ra per c.cml. The values below are
referred to the original broth as unity.
Experiment.
Bacterial
SIupernatant
Deposit.
Broth.
1. S. azeueitsat37'C.
...
...
247
0.58
2. S. aureuts at 37° C.
...
...
385
0.C61
09
0.6
3. Airial at roolmi teml)erature
4. Aierial at roolmi te pl)eratulre
15
21
...
...
Thjis observation I consider important in connexion witl
the fact that cancer frequently occurs in association witl
inflammation or subsequent to a clhronic inflammnnation.
I need only mention the constancy witlh wlichl carcinoma
of the breast is associated witlh chronic mastitis, carcinoma
of the cervix with endocervicitis and cervical erosion,
carcinoma of tle tongue with superficial glossitis, carcin-oma of tlhe vulva with leucoplakia. In the case of
sarconma, an association of tlle growtlh writh previous
inflammation is far more doubtful, but it is usually tauglht
tlhat'when a sarcoma occurs in a long bone it is apt to
arise at t-he seat of some previous injury. The- fact that
an injured bone is a locUs
mwunoris resistentiae at which
bacteria circulating in the blood stream tend to accumulate
was shown -long ago by Becker,9 and it is clear that any
SUChl l0CoU miinoris resistentiae will becomne a focus for
the accumulation of radium if bicteria be present and
also radium be circulating in the blood stream. Judging
from the experiments I lhave given above, if radium have
gained access to tlle blood stream, it will tend to accumuTABLE I.-
(dIuimii
Estimations in
Var'iouis
.4Animi1al l'issnies
including Carciniomiato.
Tissuie.
Ra ( x 10-9 mg.). Mean (x 10-9 iiig.).
~e 10 grm.
Per 100 gramls.I
8.0 (lean) i
,~~~~~~~
3 normal livers (human)
0.0
2 gall bladders (human)
2 entire miiice (normal)
...
...
4 enitire lierrings (normal)
13 herring
1
ox liver
roes
(normiial)
(niornmal)
...
Non-cancerous tissug in
Care. hepa-tis
...
...
hepatis
...
...
of
hepatis
...
to
hepatis
,,
coli
...
ventriculi
panereatis
...
Per
-
...
miiamminiae
)er 100 grams.
...
...
5.6
...
0.0
...
...
The observations
uipon
whlicll I base this statement aro
Radiumt int
(4
grains.
Disease in which the Gall Stones
were Found.
-
Care. gall-bladder
Stonies.
Quantity of Ra
x 10-9mg.).
...
Mean
(x 10-9nig.).
Il
J
0.0
linguiae
...
15.9
of
27.4
i...iiia
...
mammlae .......
0.0
vtlrae
...
0.0
...
...
0.0
...
...
...
...
...
....
~on-mua!igiiant.
-j
...
..
ventriculi.
1.0
...
..
...v
recti
3.2
...
...
..
vesicae
palacreatis
474.0
pM.6
per sample
omlitting
one case.
...
...
...
...
painereatis...
...
...
...
...
0.0
...
,,,
14,900.0*
22.3
* Excluded from
meah.
33.0
1,912.0
18.1
0.0
0.0
8.0
3.1
0.0
10.8
3.1
1.0
2.9
0.6
0.0
0.0
mediastini
fell.
of
n
ihepatis
hepatis
cerv. uteri
it
C-,ar
~arc..
,
0.0
hepatis
ventriculi.
to
113.0
et
...
55.3
sanmple.
Total Ra found.
5.6
to
...
per
225+
123+
SIP
to
142.2
...
-
23.6
5per 100 grams.
Toral Ra foiund,
237
...
mamuae.
vesicae
verage-in
-aditum,.
15.0
...
go
...
a
is foutnd
in carcinomnatous tiss8e (whether prinzary
secondaoy) oi in the tissies of carcinomatous patients.
As evidence of this statement I reproduce in Table I
my results in a number of radium estimations. It is to
be noted that special experiments conducted for -tlhe
purpose indicated that the incineration and deflagratioD
necessary to bring the animal substances into a form
soluble in dilute HCI, whereby the estimations of radiumn
could be carried out, are accountable for a loss of one-half
to two-thirds wlien dealing with 10-8 mg. radium in solu.
tion (as clhloride) distributed through 50 grams of minced
ox liver.'2 Hence, in any case in which radium is actually
found by means of the emnanation method, the amount ori
ginally present was at least twice as much as was found.
5. Whereas gall stones una8sociated with carcintoma of
the gall bladder conttain no radium or at most traces but
little outtsidle the range of experimental detection, gall
stones associated with primary carcinoma of the gall
bladder alicays contain relatively large aMounts of
it
than
or
TABLE II.-71wenti/--onc Determinations by/ the Emanation Mlethiod1
Gall
the
...
Os
coli
4. The element radium may occu,rin normal.t6sesues, but
is found on an
much8smaller q uantity
if present,
1.7
100
0.0
mammae
...
3. The alpha rays of radimn catise disappearance of
Altmnann's granules from normal cells which contain
themt,10 while Aitmai(uiin's grannles are absent from the
essential cells of mnalignant growvths.11
I will not labour this point, but the fact that tlho
granules in question are found in all varieties of nlormal
cell except unstriped muscle, collecting tubules of kidney
and squaamous epitlhelium, and are conspicuously absenit
from mialigna,nt cells and cells that lhave been exposed to
the alpha rays of radium is at least suggestive.
contained in Table II.
25.1
...
Prim-iary growth in-
ihepatis
ieiglhbourlhood.
0.1 (mean)
119.4
hepatis
coli
late at any spot of bacterial activity. The widespread
distribution of radium and the frequency of inflammatory
phenomena in the animal body (and especially in man)
render the local acculmiulation of radiunm a contingenicy by
no mueans remiiote.
If suchl accumulation occur, ceteris
paribits, a poinlt imust be reaclhed at whiclh it will induce
an increased rate of division of certain of the cells in its
_
hepatis
Care.
1.1
0.0
0.0
Metastasis inCare.
0.0
[MiAY 9, rg14
r
(cbolecystitis)
..
0.0
0.0
1.2
*The actuial experinments are recorded in the Archives of Ilhe
Middlesex Hospittil, Eleventh Cancer Report, 1912; the table was
Dublished in the Practitioner, Marchl, 1914.
MAY 9,
19143
THE CAUSE
AND CURE OF CANCER.
-1'n BEIT
M1EDICAL
JOURNAL
[
1003
I
lay considerable stress upon these observations. Not rapidity of division dominates all other functions. Thus
only are the mean differences in radium contenit of the gall we should arrive at that " interminable growtlh subserving
stones very marked, but also the very fact that one is lhere no physiological end " which characterizes the neoplasims.
dealing witlh material that resists disintegration within I see no r6ason wlhy radiations, and particularly radium
thie body argues thzat the amount of radiuimi found is the radiations, should not constitute the etiological factor of
amnount wlliclh lhas been present durinig tlle existence of all new growtths, wlhetlher carcinooma or sarcoma, wlhetlher
the calculus. In the case of carcinomatous tissue radium malignant or benign, and I commend the proposition to
wlliclh inay lhave been present at one period may easily your consideration.
lhave been lost owing to ulceration of the growtll. If no
radium be found in a gall stone one may fairly argue that
RADIO-BIOLOGICAL RESEARCH AND THE CURE OF
it has never contained radiun, but if no radiumu be found
CANCER.
in a niew growtlh the same deduLction is not allowable.
I now conme to the second of my "cancer problems
Further, not only nlay radiumn be lost owing to actual a problem wlhich, to the practising physician or surgeon,
ulceration, there is also evidence tllat insoluble salts of far transcends the other in importance, but which to the
radium (for example, sulphbate and silicate) introduced into experimental pathologist assuimx-es no such- dominant
the tissues become lost to the body. Tlhus Dominici, position.
Petit, andJaboin13 injected 1 mg. of finely divided RaSO4
.At the outset let me say that I conceive it to be the
into the jugular vein of a horse, and demonstrated diminish- duty of the experimental pathologist occasionally to put
ing quantities of radium in the urine for a period of six before the clinician a picture of the goaf towards wlhichl hie
montlhs. Similarly, I injected mice subcutaneously with should always strive-to attain and- short of wlhiclL lie
known quan'tities of radium silicate, and at varying periods should never be content with his results. That sucl
after inoculation estimated the amount of Ra in the entire clinical results sllould not reach-7 the ideal -set-by-thie
animal." I found Ra in animals dying eleven montlhs pathologist for -many years is ln the.nature of thlingas.
cli'nician does not work nwide'rlaboratory conditions'
later, but could only recover 62 per cent. of the amount
injected by the end of the first week, 27 per cent. by the the pathologist does not always give him all tIme data of
end of the second week, 21 per cent. by the end of the which1e is in need in order'to obtain the ideal resullt. As
third week, and 14 per centL by the end of the seventh an example of
I meanl may cite antitetanic sorum.
week. From these considerations one may infer that In the laboratory tetanus as a disease can be comba;ted
estimatiions of radium in gall stones probably give closely with-the greatest certainty-by means of antitetanic serun.
accurate information as to the amount of radium they In the horse
t- of tetanus by. antitetanic serum
originally contained, but that determinations of radium in meets with a large measure of success. In man the
carcinomatous tissue probably under-estimate the amount course of tetanusig practically uninfluenced by injections
of radium originally present in the cellular tissue.
of antitetanic seium. The ideal has been set in the
*6. Extosreso x radiation over long periods is liable to laboratory; the clinician has not all the data necessary
for treating the disease successfully in man, but wlho caln
be followved by carcinoma of theeaxposed parts.
doubt that in course of time the treatment of tetantus
According to PaulLazarus15 about 100eases of x-ray in man will be -carried out bym-jeans of an improvedol
carcinioma have been published, of wlhicll 50 were. in modified antitetanic serum with as great a certainty of
surgeons anld x-ray teclinicianis. The malignant growthl success as nowv obtains in the laboratory? This same
appeared four to fourteen years from tlle conmmencement proposition is eminently true in the case of cancer, -where
of action of tlle rays. Tllere is no doubt tllat the con- our knowledge is so mutch less accurate. And yet I wish
dition induced is a veritable squamous cell carcinonma, to holdl up an ideal before you, well knowing tllat at
while the occurreneo of carcinoma of the hands in persons present it cannot be attained, and, unlhappily, convinced
in miiddle life is so rare in the absence of wolk with x rays that ultimate success will only be reached over a road
that its frequenit occurrence in x-ray worliers forces us t6 that will be strewn with disasters.
associate the radiations and the carcinoma directly with
For this reason I slhall not stop to discutss the somewlhat
one anotlher. Furlther, as the result of repeated and futile question as to what constitutes a " cutre from "
intense x radiation, carcinoma of the skin hias been pro- cancer or a" cutre for" cancer. Rather shall-I- pro-eed
duced inthe rat (Clunet16). So far as concerns the actual from the laboratory point of view to try and showv yotu
production of carcinoma by means of radium, nocase has hlow radio-biological researcll indicates radium and otlher
hitherto been published. In view of the close similarity radiation. as a very special agency wherewith to treat
between the x rays and the gamma rays of radium, and of cancer; how certain disadvantages are unavoidable anid
the fact that both types of rays induce a secondary soft otlhers avoidable with our present knowledge;lhow, and
beta radiation, on impinging upon any substance capable inwhat directions, research should be conducted to turn
of affording a secondary radiation, it would appear that present failure into future success. But the ideal I shall
tlle actual production of carcinoma in the laboratory by .hold before you isthat in radium and other radiations we
means of radium is merely a question of time and hold the solution of this second'Icancer problem "-the
patience.
-cure of cancer.
I have now stated the facts upon whlich I base my
I will now lay before you the grounds npon wlhich
proposition that radiations-particularly the radiations I found thlis belief.
proceeding continuously from smnall quantities of radium1. In a stfficient dose radium and other radiations are
initiate thechanges wlhich culminate intlle production of capable
of killing every type of cell met with in cancer.
"
that whiclh we, as medical men, termii cancer." Without
It islhardly necessary for me to insist upon the inspecial attention to the point. the extraordinary potency
of radium as a force is entirelym issed, owing to the jurious effects of considerable doses of radiations upon
minuteness of quantity in which it is normally found. cells. The experience of radiologists in the matter of
Supp.osing we consider one hundred millionth of a milli- x-ray burns is clinical evidence of the fact, but in the
gram of the element as being an amnount that may laboratory evidence has been accumulated fromii so man
v
frequently be found in a carcinoma or a gall stone asso- sides, by so many authors, and to so considerable ai
ciated with carcinom a of the gall bladder. Such an extent, that it is now accepted as beyond dispute. Of
amount appears negligible, but yet that one hundred course, it is equally accepted that the different rays of
millionth of a milligram shoots intotlhe tissues in its radium, for examuple, have different capabilities in respect
neighbourhood in the course of twenty-four hours, not far of injuring cells. The different contents of energy and
from one hundred thousand alpha particles, beta particles, the different ranges of the alpha, the beta, and the gamma
and gamma rays travelling with initial velocities that vary rays indicate very considerable differences in result
m
between 12,000 and 180,000
iles a second. And this according as one or other variety of ray is allowed to act
takes no account of any secondary radiation that may be upon the cell. Thus itlhas been pointed out above that in
produced. It is to my mind inconceivable that such a order to produce stimulation in the case of Af3caris ova,
force should fail to produce changes in any cells upon one hundred times as much is necessary when alpha rays
which it acts, and there is definite evidence that it are excluded as is necessary when alpha rays are allowed
stimulates cell development. If this be so, and if this to act. From my present point of view these are details.
minute particle of radium remain indefinitely in its But I cannot give you a better example ofthe potency for
position, the laws of evolution indicate
taat from formerly destruction of radium rays than this which lies within my
normal Cells a race of cells must gradually arise in which own experience. The Ascaris ovum is the most resistant
Thle
wlhat
treatmn
1004
THE J3RITISR 1
MEDICAL JOCRNAL J
-T!HE CAUSE AND CURE OF CANCER.
IMAY
9, 1914
organismii to clhenical ageuts of wlliclh I know. It lives, adjust the dosage with radium to the exact exigencies of
divides, proceeds through changes up to the formation of the case ?
a living and vigorously moving embryo witlhin the egg3. There is some evi(lence that an active iniummunity is
case, tlhoughl actually imluersed, dturing tile days necessary
as the rcsutlt of acting utpont malignant cells
for these changes, in pure formalin. Thlouglh onily just producedI
visible with tlle naLed eye, to kill and fix it for micro- with, raditum.
Herein lies the kerniel of the wlhole question of radiosc'pie purposes no less than eiglht minutes' inmmersion in a
m:ixture of equal parts of glacial acetic acid, clhloroform, tlherapy for cancer. If radiLium rays simply destroy cells
and absolute alcohol, saturated witlh corrosive sublimate, is upon whiclh they act they are no better tllan the tlhermonecessary. And yet this saimie ninute living cell is killed cautery, the knife, or any caustic; if the rays destroy cells
by exposure to the alplha, beta, and gamma rays of 7 mg. but act with selectivity, as we have seen is tile case, tlhe
RaBr2 for ten seconds. For this variety of cell 7 mg. mnatter is better tlhouglh not entirely satisfactory. But if
RaBr2 are fifty times as lethal as a mixture of glacial cancer cells under tlle inifluence of radium-l radiations are
acetic acid, chloroformn, and alcolhol saturated witlh corrosive led to produce an antibody specific to other similar cancer
sublimate! Under such circunmstaalces you cannot fail to cells in the tissues of the patieint under treatmient, thle
agree with me that in radium we have ani agent capable of "cure of cancer " is brought perceptibly nearer.
The amount of evidence I have to adduce in favour of
killing-cancer cells when its rays are applied to tlle cells in
sufficient dose.
2. The action of radiations 1)pon cells is selective, or
conversely, all varicties of cclls are 'not equally vulnerable
to radiationls.
Of this statemnenit clinical experience on the treatmiient
of rinigworm by x rays is a good exam-ple. Witlh the
proper dose lthe cells of the hair follicle are affected to
such an extent that the lhair itself is shed, but the other
epidermal structures are relatively or entirely unaffected,
So, too, the sterility of males and of -fem ales employed in
x-ray work is evidence that tllese rays act after a selective
faslhion upon testicle and ovary, the dimiiinution in size of
the enormous spleen of leucocytllaemiiia under x radiation is
evidence of a sele2tive action upon the spleen possibly
brouglht about by way of secondary beta radiation from
the large anmount of ironi in the organ. In the laboratory
evidence for tllis selective action is even greater.
Hertwig,'7 working witlh frog's ova, frog's spermatozoa,
imnpreguated ova, tadpoles, has slhown so remarkable a
selectivity that he is able to produce in the tadpoles, at
will, a. typical disease, whiiclh he terms "r adium-disease.'"
Russ 18 has made observations whiell show that the
vulnerability of the cell of Jensen's rat sarcoma is at least
twventy-four times as great as the vulnerability of the
polymorphonuclear leucocytes. Mottram 19 has shown
that Asearis ova during mitosis are at least seven times as
vulnerable as the same cells during the resting stage, and
that the nucleus is that part of the cell upon wlhieh the
radium rays specificallv act. Morson 20 has shown that in
hliuman cancerous tissue wlhiel lhas been exposed to, say,
100 mg. RaBr2 for twenty-four hours, cancer cells are
kille,l and are unidergoing degeneration, connective tissue
cells are present in unusually large numbers, and poly.
morplhonuclear leucocytes are scattered throughout the
affected tissue.
It is clear that this selective action on the part of the
rays is a matter of funidamental imnportance. In being
able to discrimiiinate between tlle varieties of cells thle rays.
possess a fundamental advantaae over the knife, provided
that the operator lhas as great a control over tlle rays as
he hias over the knife. Unfortuinately, at the present time
this is not tlle case, and mluch remainis to be learned concerning the control of radium action before it will be even
approximately true. As an example of this ignorance,
I niay cite the different behaviour of different types of new
growth under radium treatment as carried ouLt at the
present time. Broadly speaking, one may say that the
cells of a rodent cancer or of a round cell sarcoma are
highlly amenable to radium treatment, the cells of
squamous carcinoma are fairly amenable, tlle cells of
spheroidal careinoma are somewhat amenable, the cells of
columnar carcinoma are little amenable. But who can
doubt that the plan of inserting a tube containing a
practically uniform quantity of radium (whether.as salt or
eiuanation) into all varieties of growth for practically a
uniiform number of lhours is better calculated to demonstrate the selectivity of radium radiations as regards
different varieties of malignant cell (being tlherefore a
beautiful laboratory experiment) than to bring about an
equally efficient destruction of the -malignant cells in the
a
different varieties of grot- met with in practice ? And
vet who can doubt, in view of the potency of radium
raditations in killing cells, th'at the differences noted in the
belhaviour of growtlhs treated with radium at the present
time will be obliterated when we have learnt "how to
the production of an active imnmunity is very small, but
in my opinion is cogent. It consists essentially in four
different classes of observation.
(a) Morson, Wedd, and Russ2' have shown that wlhe
mouse carcinoma cells are acted upon with a subletlhal
dose of radiumi rays, inoculation of this irradiated material
into a mouse on one side of the body prevents the growth
of a graft of untreated cancer cells made on the other side
of the body. By graduating the amiiount of irradiation the
degree of imm-iunity was made to follow the line of a
matlhel-latical curve.
Tllis experiment conforms to the observation of tlle
Imperial Cancer Research Fund 2 tllat for the productionl
of immunity in mouse carcinoma living cancer cells are
necessary, for in the experiments I have mnentioned
exposuire of tile cancer cells to a lethal dose of radium rays
comiipletely abolished their power of inducing immunity.
And I would fturther insist that when among the many
variables and unknowns of biological experimelnts any
series of results approximates to mathematical accuracy
that fact alone lends very great weight to tlle probability
of tileir inlherent accuiracy.
(b) Morson 2' hlas recorded the fact that in certain cases
in whicll a malignant neoplasm of the miiouth was
associated witi enlarged cervical glands, treatment of
the mass in the mouth with radium was followed by
very rapid diminution in size of thle mass of glands in
the neck. That these cervical glands were at a considerable distanice from the spot at which the radium
tube was introduced thlere is no doubt, lhence the dini.
nution in size of the glands can lhardly liave been
primarily due to the radium. On tile other liand, it was
not sllown by microscopic examination tilat tlle enlarged
glands were actually tlle seat of cancerous metastasis.
Nevertlieless, the records of the Middlesex Hospital slhow
tllat 80 per cent. of enlarged glands removed by operation
in malignant disease of the moutli are microscopically tlhe
seat of cancer, and the masses of glands referred to by
Morson were originally so large as to be inoperable.
Hence there appears to be a reasonable probability tllat
in tllese cases tile dimninution in size of tile glands was
due to a local destruction and absorption of cancer cells
as tlle result of time action upon tilem of an antibody
formed by tlle cancer cells of the primary mass under
the influence of the radium.
(c) Blumentlial 24 succeedled in brinaing cancer nodules to
disintegration by injectinig tilem with secretion taken fromii
an irradiated primary cancer. Tllis observation is clearly
not as definitely evidence of tlle production of an active
immunity as those I have mentioned under (a) and (b).
(d) While it is obvious tllat much additional work is
necessary before the production of an immunity by means
of radiumu can be said to be established on a firm basis,
all work that lias been done upon the subject of immllnity,
and particularly on tile subject of tissue immiiunity, coniverges to indicate that under a modified nmetabolism tlle
cancer cell will form an antisubstance to itself.
Btut thouglh there is evidence suggesting that cancer
cells may be made to produce an an-tibody to themselves,
it is probable that thlis antibody will be highlly specific.
In the case of bacteria, we have already learned the
necessity in some cases of autogenous vaccines, and in
general are aware of their greater- utility in treatment,
but in the case of cancer it would appear that this
autogenous productioim of antibody is essential. It has
been shown by the ImperLial Cancer Researchl Fund25
that an animal artificially immunized to one variety of
MIAY 9, IqI41
A
~ THE- CAUSE- AND CURE OF CANCER.
r,4
9_ _EIA
_OllA
iouse carcinoma may be as suLsceptible as a control
animiial to m-lonse carcinoma of another strain, and from
tlhis one is led to suspect that histological similarity does
nlot imply biological identity. If A. and B. are suffering
from squiamous cell carcinomata of the tongue hlistologically indistinguishable, nevertheless A.'s cancer cells
Will only be acted upon by an antibody autogenously pro.
duced in A., B.'s cancer cells will only be acted upon by
an antibody autogenously produced in B. Wlhile, tlherefore, it is possible that each patient may be induced to
form his own substance for the treatment of his own
disease, all pathological observations contraindicate the
probability of a passive immulnity in cancer. Notlhing
leads us to anticipate the utility of an "anticancerous
serum" similar to "antidiphtheritic serum."
I have already remarked upon the necessity of treating
each variety of cancer (with radium) in a manner suitable
to that specific variety; it now appears that I must go
furtlher, and say that when treating witlh radium each
case of cancer must be treated in a manner suitable to
that specific case. If the surgeon's object be to destroy
solme of the neoplastic cells outriglit, to leave enough in
a lowered state of vitality to form a sufficiency of antibody
to deal with other cancer cells outside the destructive
range of the radium, and, lastly, to produce a minimum
amount of damage to the non-cancerous tissues, it is clear
that he has before him a problem necessitating an exceedingly nice adjustment of quantity of radium, lhardness of
rays, duration of exposure to age and condition of patient,
situation and size of growth, histological type of growth,
presence or absence of metastases-to mention the most
obvious particulars. It is easy to see that since he is
using a very potent but practically unknown agent in a
disease of infinite variety, his road must be strewn with
disasters. He will find sloughing of tlle entire tumour,
slouthing of non-malignant tissues, septic absorption,
complete lack of any reaction to the radium, intense
fibrosis frequently with intense pain from pressure on
nerves or actual neuritis, temporary improvement with
perhaps complete disappearance of the growth, followed
later by a disheartening local recurrence or metastasis at
some distant spot, haemorrhage, thrombosis of veins, and
death only too often. But though they cost human lives,
they are merely the disasters of pioneer work if looked at
dispassionately; with better knowledge it is certain that
many of them will disappear, while the power of radium
rays to destroy cancer cells, to act in a selective faslhion,
to induce the formation of a specific antibody, will remain
and be utilized to better advantage.
PRACTICAL CONSIDERATIONS.
I lhave finished what may be termned the acadenmic portion of my address, but you will expect me to place before
you any information I may possess tending 'towards
attainment of this ideal I have been setting before you.
(i) Microscopic examination by a comipetent mnorbid
histologist should be made of every case subjected to
radium treatmsent. When inserting radium into a subcutaneous tumour or applying radium to a superficial
growth there is no insuperable difficulty in removing a
smiall portion for such microscopic examination. The
piece of tissuie should be placed forthwithi in 2 per cent.
formol Miller, changed daily for seven days. By this
fixative it is possible to stain for Altm-lann's granulesa matter, in my opinion, fundamental should a diagnosis
between sarcoma and inflammatory tissue become necessary. Beckton 26 has shown that all varieties of cells met
with in inflammatory tissue contain Altmann's granules,
wlhereas sarcoma cells (and epitlhelial malignant cells) are
levoid of them. I lhave hlad considerable experience of
Beckton's method, and am convinced that by its aid
(diagnosis is possible in cases, impossible to diagnose without it. So far as concerns the necessity of invoking the
taid of an expert morbid histologist, I can recall at least
two cases publish1, as examples of sueeessful treatment
ot nialignant growths by radulm in wlhicli the photoiicrogr-aphis of the authors demonstrated non-malignaut
conditious with the greatest clearness. Ne sutor utltra
ccr)eidam?-1
(Hi) The am.1zoutnt of radium)i in utse should be veriified
periodically by a com?petent physicist. I recall a long, publislhed, statistical paper expressing pessimistic views upon
the awtion of raditum on malignant growths in whiclh the
authors commenced the series of cases-with two tubes
[ TITS BJORIM
I005
_0
stated to contain rEspectively 250mng. and 150-mng. of radlituimbromiiide. Physical examnination at a later date showed
that the one tube contained 2- mgn., the other no radium
whatever. Even slhort of so appalling a circuLmstanice as
that mentioned, emiianationi miiay escape from the tuibe containing the radium salt through a minute crack iD the
tube itself, or tlle solder- with which it sholuld be hermetically sealed, the crack dleveloping in the course of
use. Under suclh circumstances the effectiice valuie of the
radium tube would be proportiolnately dIinlinished.
(iii) It shotld be recogni-zed that tlhe metabolic processes
of every patient aftet e.rposulre to a considerable (lose of
radium are profoundly modifed at least for a time. Supposing the cells of the growtlh have been killed by the
rays, a mass of dead, dying, and disorganizing tissue is
being absorbed into the body at large during the period
over whiclh the irradiated muass is seen to be diminishing in size. Frequently suell climinution in size is
very rapid. It appears to me quite possible that somlle
of the deatlhs that have occurred shortly after intense
irradiation of a very large tumnour may hiave depended
upon the fact that a considerable quantity of higlhly
toxic material was suddenly thrown lupon a systemii
already enfeebled by the disease. And this, without
consideration of the many clhanges that lhave been
described as occurring in the body (for example, blood
changes) as the result of irradiation. The sense of " wellbeing " that usuially obtains during the first few days after
exposure of a growth to a considerable dose of radium is
quite compatible with a limited autointoxication.
For the same reason it would appear that sturgical
operations should not be undertaken after exposure of the
patient to radium until sufficient time has been given for
a full re-establishment of general health. I have heard 'of
several cases in whiclh surgical removal of a formerly
inoperable growth which had been brouight within operable
limits by radium was followed by deatlh of the patient not
wholly explicable on ordinary surgical grounds. The
tenmptation to operate in such cases must be very considerable, but the longer it can be resisted with safety to
the patient the better the prospect.
For the same reason, too, repeated doses of irradiation
should be given with great care and with sufficient
intervals for recovery. This point is recognized by
radiologists (cf. Lazarus, Berl. klin. TVoch., 1914, Nos.
5 and 6).
(iv) Treatment with radium should not followv inmmiediately itpon operation. In spite of the fact that x-ray
treatment following on operation appears to be beneficial
in many cases, tlle very opposite is true witlh radium
treatment. In the case of radium the explanation is not
difficult. The powerfully destructive action of the radium
rays is brought to play upon normal tissues (already
damaged by operation), in the midst of which outlying
foci of malignant cells are suspected to be present. Not
only are those normal cells damaged whose duty it is to
bring about the death and absorption of isolated foci of
malignant cells (cf. Handley's lymphatic fibrosis 27), but
also a more or less extensive necrosis of non-malignant
(normal) tissue is produced with its attendant autointoxication and necessity for removal.
(v) If radium treatmient of a mialignant newv growth, be
decided 'upon, stch treateentshofld rot be preceded by
complete removal of t7he mnain part of the growth. To a
certain degree this proposition is the converse of the last.
It is clear that if a tube of radium be placd in the midst
of unremoved growtlh the danger of injury to surrounding
normal tissues is less. But- a mu-ch more important consideration underlies the advice. If maligniant cells be
necessary for the production of an autogenous antibodv,
and if such cells as will form the antibody inust be stilIl
living (tlhough witlh a profoundly altered metabolism), tjie
chance of their production by means of the radium will
largely depend upon the -diameter of the mass of
malignant cells through wlhich the radium rays are able
to act. Ideally, the m-'ost peripheral cells of the primary
mass should be so reduced in vitality tlhat they would lead
to the production of antibody suffidient td deal with any
malignant cells that had been ca'ried from the Primary
mass to distant parts before irradiation. In practice
nothing approachiing stuchlan ideal result is likely to
obtain if all but a' few malignant cells be removedl
prior to irradiation. Naturally, too, 'the dose of irradiation
meaning thereby that complex of quantity of radium,
IOO6
MEDICAL JOURNAL]
RADIUM IN TREATMENT OF MIALIGNANT DISEASE.
length of exposure, nature and thickness of screen-necessary to produce the ideal result must vary infinitely witl
thte infinite variety of growtlhs presenting tlhemselves for
treatmnent. It is a hardI saying, but the surgeon usitng
radium must steer between the Scylla of (a) extensive
dlestruction of normiial and malignant tissue, witlh (b) no
production of auto6genous an-tibody, and the Charybdis of
(c) inssufficiently modified mialignaint cells, -wlich are
injured jtust enougli to beconme " latent," anid to lead to
local recurrence at some later date, and of (d) malignant
cells actuallys stimulated to -an increased rapidity of
growth. It is not very probable- that every- practitioner will .be able to- carry otut radium treatment of
malignant disease successfullv.
future, for th7e
(vi) Whatever mttay be the case i
present radiuml treatment of 2nalianant disease should be
confined to those cases for wvhich modern -surgery cannot
offer a fair prospect by operation. In the oase of frankly
inoperable mialignant disease it is unnecessasy to urge at
the present day that radium should be tried. In- spite of
disasters, disappointments, recurrences, pain: from fibrosis
so severe that the last state of the patient is worse than
the first, a number of cases remain on record in which tlle
result lhas been remarkably good. Without doubt the profession holds in radiuit an agent for the treatment of
inoperable cancer such as it has never held before. But if
this be truie for inoperable cases, should not radium be
given- a clhance in preference to operation for cases in
*which surgery is notoriously unsatisfactory, thougll not
impossible? .-Are the prospects of a patient witli malign:ant,disease of the.tonsil or periosteal sarcoina any worse
if he be treated with radium: than if he be treated by
operation ? Does the small procedure entailed by the
intsroduction of a tube of radium into the mass of growtb,
as against the large.procedure of an -extensive- operation,
count for nothing in the well-being- of the patient? At
the very least, slhould not the patient under such circumstances be presented with the two alternatives and allowed
to make his choice ?
But this is the furthest that one can go. At present,
-where modern surgical operation can offer a fair prospect
of satisfactory result, the knife must be recommended in
preference to every other agent, and this is as true for
recurrences as for the primary disease. It must be remembered, however, that radium has only been known for
sixteen years, and has been used in medicine for a far
shorter period, whereas tlle surgeon's skill with tlle knife
is the product of centuries.
My task is finished. With feet sometimes on sure
grounid, sonmetimes on less certain ground, I lhave tried to
bring to youir eyes visions wlhich eight years' radio-biological
work have brought to my own. I see cancer as a protean
manifestation of purposelessdisorderly cell growtth brought
into existence by the. long-continued action of a cell
stimulant, and I see,in radium and radiations an agenev
sufficient to produce cancer. But just as in the case of
diphltheria the agent which produces the disease is also
the agent wllhereby the specific cure for the disease is
elaborated, so I am prepared to see cancer caused by
radium and cancer cured by radium. Probably it matters
little wlhether I foreshadow -the true solution of the " cause
of 'cancer " problem, but no man -could wish for a greater
hionour than to lhave had a share in foreshadowing the
true solution of, the "cure of cancer" problem. For the
sake of humanity it is.to be hoped that those who believe
in the essential capability of radium to "cure" cancer
are right.R
REFERENCES ..
1 BRITISH MEDICAL JOURNAL, June 19th and 26th, 1909. 2 Arch.
Middlesex Hosp., Twelfth Cancer Report, 1913, p. 47. sJourut. Path.
and- Bact., vol. xiii, 1909. p. 330. 4 Sitzungsber. d. K. Acad. d.
Wissensch. in Wient. Math-Naturwv. Kiasse. Bd. cxxi, Abt. i, Marz,
1912. 5Com2ptes rentds, T. 157, 1913, p. 1082. 6 Arch. liddlesex Hosp.
loc. cit., p. 17. 7Ibid., Eleventh Cancer Report, 1912. p. 128. 8Ibid.
p. 113. 9 Deut. nted. .Woch., 1893. 10 Arch. Middlesex Hosp., Tenth
Cancer Report, 1911, p. 99. 11 Ibid., Eighth and Ninth Cancer Reports,
1909-10. 12Ibid.. - Twelfth Cancer Report, 1913,- p. 95. 13 Conmptes
renddus. T. 120, p. 726, 1910. 1t Ar-ch. Middlesex HOsp., Twelfth Cancer
Report, 1913, p. 92. 15 Be-l. kli.t. Woch., 1914, Nos. 5 and 6. 16 Re.cherches exp. sitr les tutmeinrs malignes, Paris' 1910. 17 Arch. f. meikr.
*Anat., Bonn, 1911, Bd. 77, 2te Abt.. pp. 1-95. 18 Cf. Arch.' Middlesex
..HQsP., Eleventh Cancer Report, p. 43 and Twelfth Report, p. 128.
19Ibid;, Twelfth Report, 1913, p. 98. Proc. Roy. Soc. Me., Section
-of Pathology, March, 1914; 21Jiuaryllmeeting of PatholoXgical Society
of Great Britairt and ireland (in the p)re.ss). 2-2 Haaland. Proc. Roy.
Soc., 1910. B. vrol. 82, p. 293. 23 Loc. cit. 24 Ber. k^iml. WoC., 1913.
No. 50.- 2 Russell, Fifth Scientific Report, Imlperial Cancer Research
Fond-, 1912, p. 1. 26-ArcJh. Middlesex Hosp.. E:ighth Cancer Report,
1909. p. 182, and Ninthl Report, 1910, p. 115. 27 Ibid., Fourth Cancet
Report, 1935, p. 191.
[MAY 9, 1914
RADIUM IN THE TREATMENT OF
MALIGNANT DISEASE.
BY
JAMES R. RIDDELL, F.R.F.P.S.,
MEDICAL ELECTRICIAN, ROYAL INFIRMARY AND ROYAL CANCER
HOSPITAL, GLASGOW.
THAT radium.exercises a profounid influence on tlhe lhunian
tissues inliinicable to the existence of'canceir is no lonaer an
open question. It has been demonstrated'again and again,
,and nanjerouq, cases. are, on record of tlhe rapid recession
anid disappearance of malignant tumours under its influence.
It is, uinfortunately, also true thlat much more numerous
are the cases' in wlicli tlhe. beneficial influence is not so
apparent, and that in tlle vast majority of cases treated
tile patients ultimately succuinb to tle disease. Nevertlheless, sufficiently numerous are. the records of complete
disappearance of malignant.tumours after r'adiuin applications to satisfy the most sceptical tllat the' effect is attributable to tile radium and not4oa sonme of those unknowyn
causes wlliell apparently do, on extremely rare occasions,
make a canicer undergo spontaneous cure. Tile results of
radium tlherapy in malignanit disease are suclh as to justify
tlle hlope tlhat, as our knowledge of its action and of the
means7 of modifying and controlling that increases, there
will be an ever-increasing proportion of cures.
Radiumn constantly emits a chemically inert gas known
as radium emanation; this rapidly breaks up, giving rise
to very short-lived bodies wlhiell give off beta and gamma
rays; all these bodies, taken togetlher, constitute wlhat is
known as "the active deposit," and it is from this tllat tlle
radiations used in medicine are obtained.
WVhen tile radium is sealed in an airtight container tile
emanation is given off at a steadv rate, consequently that
containier or applicator will always give a certain definite
dose in a given time. If tlle radium is not sealed up but
is in solution it is possible to extract all the emanation in
a sliort time. Tlhe container of this emanation will tllen
emit tlherapeutically active rays until all the emanation is
used up. The radliurm solution is now exhausted, and it
will take three weeks to recover itself completely. It
will have recovered its activity to half value in four days.
Inasmuch as the therapeutic rays are produced by tlle
emanation, it cannot be material whether treatment be
carried out by the emanation container or by tIle sealed
radium container, provided allowance be made for tile
progressive fall in value of tlle former-a fall amounting to
20 per cent. in tlhirty lhours. Dosage is regulated by (1)
the quanitity of radium, (2) the density- per unit area, (3)
tue lengtlh of timne of exposure, and (4) the amount of
screening interposed between the part treated and the
radium.
For external application the container is usually applied
close to tile skin. With regard to the quantity of radium,
it must be remembered that wllat is called radium is i-n
reality a mixture of a radium salt witlh other substances,
suchl as barium salts-the proportions usually being 1 of
the radium salt in 5 of the mixture. The degree of purity
does not matter, as the dose is calculated on tlhe actual
amouiit of radium present in tile mixture.
The density per unit area is a fixed quantity for eaclh
applicatoi. But within limits an applicator of a, certain
density can be made equivalent to one of less density by
being placed at a greater distance from the part to be
treated. Tile length of time varies from a few minutes,
where tlhe density of tlle applicator is great and lno
screens are used, to twelve or even twenty-four hours
when Ileavy screens are used.
Put very generally, an applicator having a density of
1 cg. to 1 sq. cm., screened only by thin rubber and
several layers of paper, sucll as might be used for tile
treatment of port wine marks and superficial naevi,
would give in ten to fifteen minutes a dose wlicih would
produce an inflammatory action. The same applicator,
if screened witlh 0.2 mm. of silver and paper, could be
applied for peihaps fifty to sixty minutes. When it is
intended to act, not on the skin, but tlirotugl it, on tlle
deep-lying tissules,. screens are- used of silver or lead
1.5 or 2 mm:. thick. WVithl such screens the application
may withl safety last twelve to eighteen hours.
Whenl rays pass through a metal filter or screen, secondary
rays are set up. The penetrating power of these is very