Download in the Treatment of Cancer* Radioactive Isotopes and Nuclear

Radioactive Isotopes and Nuclear Radiations
in the Treatment of Cancer*
JOHN H. LAWRENCE AND CORNELIUS
(Donner Laboratory and Donner Pavilion,
It is now @20
years since we began to use arti
ficially produced radioactive isotopes in cancer re
search and in medical research. Actually, our first
therapeutic trials were in 1936. In the early days
the hope was that at the end of @0
years one could
report outstanding examples of selective localiza
tion of radioactive compounds in neoplastic tissue,
making it possible to give the tumor tissue many
times more irradiation than the surrounding, nor
mal tissues.
Up to the present moment, investigations with
only two radioactive isotopes have given us impor
tant therapeutic applications in hyperplastic and
neoplastic diseases through selective localization.
These are radiophosphorus
in the treatment
of
polycythemia
vera and radioiodine in the treat
ment of the thyroid hyperplasia of Grave's disease
and in the palliative treatment of certain thyroid
cancers. However, one who has worked in the field
from the beginning and who is asked to sum up his
experiences can't help saying that the therapeutic
achievements have been disappointing;
but even
in the early days we believed that the greatest
contribution
of radioactive isotopes in the field
of medical and cancer research would lie in tracer
applications,
and we have devoted most of our
energies to the latter.
Even though the achievements in prolongation
of life and cures in cancer have not been great so
far, one should not dismiss too lightly the con
tributions
of artificial radioactivity
and nuclear
radiations in cancer therapy. The clinician should
not underestimate
the importance of relief from
pain and extension of comfortable life, and here
their value is well established.
The importance of the products of nuclear phys
ics in cancer therapy is pointed up by the fact that
demands for radioactive isotopes in medical and
biological research have risen rapidly in the past 10
years. The shipments of radioactive isotopes from
Oak Ridge National Laboratory have risen from
less than 500 in 1946 to almost 1@,000 in 1954.
Seventy per cent of the total dollar value of all
* Presented
topes and
of Cancer
presented
appeared
as
part
of
the
Symposium
on
Radioactive
Iso
Cancer at the meeting of the American Association
Research in San Francisco, April 16, 1955. Papers
by David M. Greenberg and by Jacob Furth have
in the August, 1955, and the January, 1956, issues of
Cancer Research, respectively.
University
A. T0BIAs
of California,
Berkeley, Calif.)
shipments is for medical use, and one-third of
these shipments are for cancer therapy. For in
stance, there are 50 medical groups in the United
States using radioactive colloidal gold and radio
active colloidal chromic phosphate for interstitial
infiltration
in various types of cancer, such as
prostatic, uterine, and bronchogenic. Two hundred
fifty groups are using radioactive gold, chromic
phosphate, and yttrium colloids in the treatment
of cancer metastasized to the pleural and perito
neal cavities. There are 400 groups using iodine
181 in the diagnosis and treatment of hyperplastic
and neoplastic thyroid disease and 889 groups
using
@32
for the treatment of polycythemia vera
and chronic leukemia. During 1954 there were
over 5,000 shipments of radioactive iodine from
Oak Ridge to individual users, over @,500ship
Inents of radioactive phosphorus, and 6@ ship
ments of radioactive gold. At the present time
there are 30 cobalt teletherapy units in the United
States in use for external irradiation therapy of
cancer with high energy gamma rays, and 50 more
are being planned (1).'
Most of the isotopes which have been used in
the therapy of hyperplastic or neoplastic diseases
in the form of internal, intracavitary,
interstitial,
contact, tele, or fission radiation are listed in
Chart 1 in the order of increasing atomic number.
Early work by Kruger in this laboratory
15
years ago (@5) and by Zahl at al. (59), followed by
the uranium fission experiments by Tobias at al.
(55), more recently has led to the trial of boron-lO
in the treatment of brain tumors, particularly glio
blastomas, the radiation being derived from the
fission of the boron nuclei after slow neutron cap
ture (7). Kruger bathed tumor slices in boric acid
solution in vitro and then irradiated them with
slow neutrons, causing fission of the boron nuclei
into lithium and alpha particles. The ionization ob
tained is relatively densely localized, the particles
traveling about one cell diameter (55). After borax
containing boron-lO was injected intravenously
into patients with brain tumors who were then ex
posed to soft neutrons from the atomic pile, Farr,
Sweet at al. (7, 13) have been able to deliver a few
‘Atthe International
Conference
@nthe Peaceful Uses of
Atomic Energy held in Geneva in August, 1955, the author
learned from Professors Modestov and Fateyeva that there are
150 such units now in operation in the Soviet Union.
185
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Cancer Research
186
hundred roentgens to the tumor tissue by such fis
sion energy, but this is probably insufficient to give
real therapeutic effect. Pathological studies of eight
of the first ten patients treated at Brookhaven
showed changes suggestive of irradiation effects in
three patients; however, large areas of viable tu
mor were found in all cases (13). More recent in
vestigations by Kruger have shown that the con
centration of boron in the boundary between nor
mal and tumor tissue in glioblastoma multiforme
tumors in mice can be increased by injection of
palliative treatment
of advanced cancer of the
bladder, but the survival time is not available for
a large series of patients (58). The beta- and gam
ma-emitting isotope Na24 has also been tried in the
treatment of chronic leukemia, but the method has
not found wide usage, since there is no selective
localization of sodium.
The first example of a successful application of a
radioactive isotope in therapy was the treatment
of polycythemia vera with @32•
Enough experience
has been gained over the past @20
years to allow one
SOME OF THE THERAPEUTIC
USES
OF RADIOACTIVE
ISOTOPES
Glioblastoma multiforme
Bladder carcinoma
Polycythemia, chronic leukemias, breast cancer
Control of oscites and pleural effusion in metastatic
Deritoneal and aleural carcinoma
.@
carcinoma,
cervix
carcinoma,
bronchogenic
carcinoma
erkeratosis, basal cell carcinoma, squamous cell carcinoma
‘iancarcinoma
carcinoma, naso-pharynx tumor, maxillary tumor,
esophaqeal carcinoma, uterine body carcinoma
carcinomaDeep-seated
carcinoma, cervix carcinoma, bronchogenic
1 1
—@Bladder tumors
:...Prostate
carcinomaOvarian
carcinoma5r90Pterygium,
vernal conjunctivitis, vascularization of cornea
Hepatomegaly and splenomegaly in advanced leukemia
@
I
I
I
—
J
I
Other isotopes
I•.'
—
Thyroid
cancer
angina
pectoris
congestive
heart
failure.
hyperthyrodism
Hepatomegaly and splenomegaly in advanced leukemia
Control of ascites and pleural effusion in metastatic carcinoma
Prostate carcinoma, cervix carcinoma, bronchogenic carcinoma
1
I
used in therapy:
CHART
Calcium, Chromium, Gallium, Arsenic,
Astatine,
Ruthenium
1 .—Some
therapeutic
applications
Evans Blue dye containing boron-lO in the mole
cule (@6). Although the localization of the radio
isotope achieved by use of the dye is 30 times that
obtained after injection of boron-lO as borax solu
tion, the localization is greatest at the brain-tumor
interface and is not uniformly distributed through
out the tumor tissue. Consequently,
there is still
insufficient localization in tumor cells to provide
the needed radiation. However, the use of such
boron-containing
dyes should be explored. If fis
sionable material can be synthesized into com
pounds that will give great selective localization in
neoplastic tissue, there is little doubt that great
therapeutic benefit can result.
Sodium-@4 and bromine-8@ have been used in
the form of fluid instillation into the bladder for
of radioactive
Thulium, Lanthanum,
Ceseum,
isotopes
to say that the condition can be satisfactorily con
trolled by @82
(@9). The survival of patients with
polycythemia treated by @32
is about equal to that
in cases of pernicious anemia treated by liver or
vitamin B@2and diabetes mellitus treated by in
sulin (Chart
@),and is superior to any increased
survival rate yet achieved in such cancers as
breast or prostatic cancer with newer methods of
therapy (Chart 3). The median survival in pa
tients with polycythemia
vera is 14 years, com
pared with a survival of approximately
@0
years for
an age-matched group of the general population.
Since 1936, when
@32
was first used in the treat
ment of chronic leukemia (30), thousands of pa
tients have been treated. As shown in Chart 3,
approximately
50 per cent of the patients with
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
LAWRENCE
AND
ToBrJ1s—Radioactive
Isotopes
chronic lymphatic leukemia treated by P@ will
survive over 5 years (@8). This is somewhat better
than the 8urvival in 1,600 cases treated by conven
tional methods reported in the literature review by
Osgood (81).
Between 1985 and 1940, in the early days of the
radioisotope work, we attempted to treat a group
of patients with breast cancer and prostate cancer
metastatic
to bone by means of intravenous
or
oral administration
of @32
or Sr89 (@7, 80, 40). It
had been demonstrated
that strontium, like cal
cium, localized to a high degree in bony tissue with
less uptake than P@ in soft tissue. However, the
results were not exciting, and this work was aban
doned when it became evident that it would be
impossible to deliver sufficient beta radiation to
the bony lesions without causing severe marrow
depression. Recently, Friedell (11) and others have
re-introduced
@32
in this form of therapy and
found again that there is some relief of pain and
occasional evidence of healing. This type of ther
apy may have a small place in the palliation of
cancer metastatic to bone.
in
the
Treatment
of Cancer
187
is pipetted onto it, and the plaque is then applied
directly to the lesion. In the case of basal-cell car
cinoma, a dose of 34,000—36,000 rep is delivered to
the surface, and @0,000—@,500
rep delivered to the
first millimeter depth in a period of 48 hours. This
method is producing results equal to those of any
other of the more conventional methods now in use
for the treatment of superficial skin cancer.
Radiophosphorus
as colloidal chromic phos
phate (@1),first used by Jones et at. (fl), as well as
YEARS
CHART3.—Survival in cancer, leukemia, and polycythemia
compared with life expectancy in the general population (thin
line). For polycythemia
vera the dotted line represents the life
expectancy after conventional forms of therapy (56) and the
thick black line shows our results after treatmentwith P―(@9).
For leukemia, the thick black line shows life expectancy in our
patients with chronic lymphatic leukemia treated with P―(Q8)
compared with average results in chronic myelogenous and
lymphatic leukemia reported in the literature
(dotted line)
(37). For breast cancer the increased survival achieved with
radical mastectomy (thick black line) over that following non
radical procedures (dotted line) is shown (49). The survival
rate in cancer of the prostate following the Huggins method of
orchiectomy and diethylstilbesterol
(thick black line) is corn
pared with survival prior to Huggins' work (dotted line) (36).
(0
z
>1
-j
z
I—
LU
LU
0@
YEARS
CHART
L—The
@32
compared
with
survival
the
in polycythemia
survival
with insulin and pernicious
vitamin B-1Q.
in diabetes
anemia
treated
vera
treated
mellitus
with
treated
with liver and
Friedell and associates have also made Sr9°ap
plicators for use in the treatment
of superficial
tumors of the eyelids, conjunctiva,
and cornea!
ulcers (1@). The treatment of skin cancer and hy
perkeratoses by @32
contact therapy (31) has added
another successful method for the treatment
of
such lesions. Since 1943 Low-Beer has treated 350
hyperkeratoses by this method with a 5-year eradi
cation rate of 98.8 per cent. Of the 190 basal-ce!!
carcinomas treated, 97.6 per cent have been eradi
cated for longer than 5 years. Also, 47 hemangio
mas have been successfully treated by this meth
od. A small plaque of blotting paper is cut to fit the
size of the lesion, the desired amount of Na2HP32O4
colloidal radiogold (p2,14, @4)and radioyttrium,
is
being currently given to patients suffering from
pleural and ascitic effusions in metastatic
car
cinoma. This application of radioisotopes consti
tutes an important addition to palliative cancer
therapy. Although there is no evidence that such
therapy prolongs life, there is little question that it
relieves pain in many instances and slows down the
accumulation of ascitic and pleural fluids, so that
paracentesis is often unnecessary or need be done
at less frequent intervals.
Colloidal chromic radiophosphate
and radio
gold are also being used interstitially for the treat
ment of carcinoma of the prostate before distant
metastases develop (8, 9, 46). The beta radiation
from these colloids allows a large tumor dose of
radiation to be given without damage to surround
ing tissues, as might occur with conventional x-ray
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
188
Cancer Research
therapy. Some workers point out the fact that
chromic radiophosphate
has an advantage
over
radiogold in that the former emits only beta rays,
and less elaborate radiation protection measures
are needed. However, other workers believe that
radiogold gives a somewhat better therapeutic ef
feet because the greater penetration of the gamma
radiation will, with the beta radiation, in effect
give a more uniform dose. Radioactive Y@ (@3)
and chromic phosphate (45) beads and radon im
plants (10) have been used for destruction of the
pituitary in certain types of cancer. The tech
nics for distributing radioactive materials in tis
sue may be improved in the future in some cases
by the intra-arterial
injection of the radioactive
materials.
In 1948 we used colloidal chromic radiophos
phate in the treatment of a group of patients with
chronic leukemia, polycythemia
vera, and also a
group with marked splenomegaly or hepatomegaly
from miscellaneous causes (6, @).We found these
results no better than those following P@, as
Na@RP@O4, and, because of the chances of getting
the radiocolloid outside the vein with resultant
radionecrosis, we have more or less abandoned the
use of the various radiocolloids for the treatment
of this group of diseases. Gofman and associates
used many other radiocolloids in the same group
of diseases and arrived at the same conclusion (6).
Cobalt-60 is being used in intracavitary
and in
terstitial therapy of nasopharyngeal and maxillary
tumors and uterine, prostatic, bladder, and bron
chogenic carcinomas. In general, it is too early to
evaluate the results in comparison with those
achieved by conventional means of therapy. Hin
man and co-workers (18, 47) treated 85 patients
with bladder tumors by intracavitary
irradiation
using cobalt-60. They report that in four of nine
patients with tumor confined to the mucosa the
lesions were destroyed, but most infiltrating le
sions were only temporarily arrested.
The cobalt bomb teletherapeutic
units are of
wide interest now and are being used as substitutes
for @00kv. x-ray equipment in the treatment of
deep-seated
tumors. Radiocobalt
provides the
gamma ray source in these units, but other gamma
ray emitters such as cesium are also being used,
especially in Great Britain. These teletherapeutic
units have certain advantages over x-ray equip
ment, such as cost and mobility, but one cannot
expect much improvement in end results over con
ventional methods which use x-ray or other gam
ma ray sources.
Since the first therapeutic
use of radioactive
iodine (15, 16, 17, 80), it has been widely applied
in the treatment
of hyperplastic thyroid disease
or Grave's disease; indeed in many hospitals
it is entirely replacing surgery, and remarkably
good end results are reported (5, 34). In the
case of thyroid cancer, however, it is rare that
radioiodine will localize sufficiently in a metastatic
lesion to give a good therapeutic
result or cure,
even after complete thyroidectomy
or after a long
course of propylthiouracil
or thyroid-stimulating
hormone (43). The cases in which there is a good
uptake of radioiodine, however, give one increas
ing confidence that if selectively localizing corn
pounds can be found, lasting benefits might be
obtained
in advanced
cancer of other types
also.
Figure 1 is a gamma ray picture of the localiza
tion of I's' in the body of a patient with thyroid
rnetastases obtained in the first whole-body scan
ner now so widely used. This whole-body scintilla
tion scanner, developed by Anger and Tobias (8)
for photographing gamma ray-emitting isotopes in
the body, is shown in Chart 4. It consists of a series
of scintillation counters within lead cylinders. The
gamma ray energy from the isotope within the
body is converted to light energy and photo
graphed with a polaroid camera as the body is
scanned. New methods for visualizing the distri
bution of radioisotopes in vivo, such as the one de
scribed here or the gamma ray pinhole camera
(85), are expected to be of indirect use to therapy
through more accurate localization of tumors. The
patient illustrated in Figure 1 was a 68-year-old
male with thyroid metastases in the left upper
arm, the chin, the sternum, the hip, the thigh, and
the ribs. Interestingly enough, two of these lesions
were not discernible by x-ray examination,
yet
they could be picked up by the scanner. This
method of locating tumors would of course have
important
diagnostic
applications
if localizing
compounds emitting gamma rays could be found
for other types of cancer. This particular patient
had the largest uptake of radioactive iodine in
metastatic lesions that has come to our attention.
Comparative
counting rates over the tumor and
an equal volume of normal tissue showed that the
tumor concentration
of I's' was as much as @00
times that in an equal volume of normal tissue.
During therapy with an oral dose of 100 mc. of
J131,
as
much
as
100,000
rep
in
radiation
was
deliv
ered to the neoplastic lesions. Prior to surgical
thyroidectomy
there was no uptake in these me
tastases. Now, 6 years later, this man is symptom
free, and, at the age of 74, he is an example of the
good result that can be obtained with isotope ther
apy when there is a high selective uptake by neo
plastic tissue. Uptake in metastases can be stimu
lated by surgical thyroidectomy,
and administra
tion of propy!thiouracil
and thyroid-stimulating
hormone are also sometimes helpful in increasing
iodine uptake in metastases
(48). Another diffi
culty encountered in the treatment of metastatic
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
LAWRENCE
AND T0BIAS—Radioactive
thyroid cancer with radioiodine is that the radia
tion dose may not be uniformly distributed in the
tumor tissue. Surgery and x-ray continue to be the
primary tools for treating thyroid cancer.
The high selective localization of iodine in thy
roid tissue and also the selective uptake of radio
phosphorus by the bone marrow and blood-form
ing tissues allow us to deliver relatively high doses
of radiation to specific tissues. Perhaps in our
present state of relative ignorance regarding the
metabolic differences between the cancer cell and
normal cell, it is too much to expect that a radio
active compound can be found which will localize
in cancer cells selectively enough to give V5, 50, or
more times the radiation than normal cells will
SCHEMATIC
Isotopes
in
the
Treatment
of Cancer
189
planted melanosarcoma. There was some localiza
tion in the melanosarcomatous
tissue, but there
TYROS/NE
HOQI' —C--C—C—OH
4@O
ii
H NH2
was an appreciable uptake by the adrenal and
thyroid glands, since tyrosine is a precursor of the
hormones produced by these tissues.
The metabolism of stilbamidine containing C14
was studied in multiple myeloma, and, while it did
DIAGRAM
CHART4.—Diagram of the scintillation
receive. If such is to be found, the ideal isotopes to
be built into the localizing compound would seem
to be hydrogen-S or carbon-14. The latter provide
relatively soft beta rays traveling only a few cell
diameters in tissue.
Many workers have attempted
to synthesize
compounds
containing
radioactive
carbon and
other radioelements for selective localization. Reid
and Jones (44) made C'@-labeled tyrosine and in
jected some of it into animals carrying a trans
scanner (from Anger et at.)
localize in the myelomatous tissue, there was an
even greater uptake by the liver.
These examples are typical of the many coin
ST//JAM/DINE
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
Cancer Research
190
pounds that have been synthesized—localization
of the radioactive compound is not sufficiently lim
ited to the neoplastic cells to permit a good dose of
radiation to be given without damage to normal
tissue.
Some of the most interesting current investiga
tions on selective localization are typified by the
studies of Pressman and associates (41) . After im
munizing animals to various normal tissues and
neoplastic tissues and then adsorbing radioactive
iodine to the antibodies, they have been able to
demonstrate some localization of these antibodies
•
Chronic lymphatic leukemia (131)
Chronic myelogenousleukemia (138)
•
Breast cancer, radical mastectomy
(125, Univ.of Rochester)
•
Stomach cancer (2772, Mayo Clinic
Lung cancer, pneurnonectomy
(202, G.A Mason)
0
z
>
>
U)
I
z
w
C.)
3 This
LU
a.
YEARS
CHART 5.—Survival rates in chronic lymphatic leukemia
treated with P@ (@8), in breast cancer treated by radical
mastectomy
(49), in stomach cancer treated by gastric resec
tion (57), and lung cancer treated by pneumonectomy (33).
in the various normal and neoplastic tissues. More
recently Bale2 has achieved tumor localization of
such antibodies 15 times greater than that of any
normal tissue, indicating that this approach may
be a very hopeful one (4, 50).
The therapy of cancer continues to be based
primarily on early diagnosis, surgery, and post
operative x-ray therapy. Radioactive isotopes and
nuclear energy have not yet added importantly to
the armamentarium
of cancer therapy, but the
relatively poor survival in cases of deep-seated
cancer impels investigators
to make heroic at
tempts to relieve these people and extend their
lives. As can be seen in Chart 5, the 50 per cent
survival in the case of breast cancer, the most com
mon type of cancer in women between the ages of
40 and 60, lung cancer, and stomach cancer is
approximately
8-5 years.
One of the real advances in cancer therapy has
been the revelation of the relation of hormones to
certain types of cancer, including the effects of
oophorectomy,
adrenalectomy,
and hypophysec
tomy on advanced breast cancer (4@). Two ex
amples in particular are the work of Huggins in the
field of prostate cancer treated by orchiectomy and
diethyLstilbesterol (19), and the treatment of met
* W.
astatic breast cancer by adrenalectomy
(@0).
Olivecrona and associates were the first to report a
remission in metastatic
breast cancer following
hypophysectomy
and have recently reported the
results of this form of therapy in a series of 30 pa
tients (8@2).Other workers in this field have esti
mated that approximately
50 per cent of patients
with advanced breast cancer have tumors which
are hormone-dependent,
and approximately 50 per
cent of the patients of this type undergoing sue
cessful hypophysectomy
will show some evidence
of healing (38, 89). Apparently, the response is in
dependent of the cellular type of mammary tumor,
and whether the effect is always mediated through
the ovaries and adrenals or whether there is a pri
mary pituitary factor is not yet known.
With the hope that hypophysectomy
could be
achieved by irradiation, for 15 months we have
been making such attempts
using a somewhat
unique form of irradiation from the 184-inch cy
F.
Bale,
personal
communication,
“Atomsfor Peace Conferences,― Geneva,
presented
August,
1955.
at
work
is
a
projection
of
the
animal
studies of Tobias et at. (51, 54), who achieved hy
pophysectomy
in the rat, dog, and monkey with
beams of high energy deuterons or protons. One
unusual feature of the beam is its pencil-like nature
with very little scatter, unlike a similar beam of
x-rays or gamma rays. Another unusual feature of
these beams is that there is a relatively greater
depth dose compared with surface dose. The com
parative doses at the surface and depth for @00
kv.
x-rays, 16 mev electrons, and 190 mev deuterons
are given in Chart 6. The @00kv. x-rays fall off
markedly at 10-cm. depth, and the electrons from
the betatron or synchrotron also fall ofT consider
ably, but the deuteron irradiation rises to a peak
at 14 cm., so that the depth dose is approximately
4 times that entering at the surface.
Two animals with mammary cancer are shown
in Figure @.
The one on the left is the control, and
the one on the right has been irradiated by passing
the beam through the chest of the animal from the
opposite side, localizing it on the tumor. In other
words, it is possible to deliver energy in the depths
of tissues with relatively little skin effect using this
form of radiation. Tobias et at. have applied this
beam to the pituitaries of rats, monkeys, and dogs
and have been able to remove the pituitary by this
selective form of external irradiation, producing
atrophy of all the target organs, effects paralleling
those of surgical hypophysectomy.
Four litter
mates are shown in Figure 8. The second from the
left has had surgical hypophysectomy,
and the
third from the left irradiation hypophysectomy.
The animal on the left has been subjected to hypo
thalamic irradiation which produced obesity, and
the animal on the right is the control.
@Thiswork is supported by the Atomic Energy Commission,
the California State Cancer Fund, and the Donner Foundation.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
LAWRENCE
AND
ToBJ.@&s—Radioactive
During the past year this beam has been applied
to the pituitaries of patients with advanced breast
cancer and to two patients with leukemia, one hay
ing an associated diabetes. This work has been the
subject of two previous reports which give much
more detail (5@2,53). The patients with cancer
have previously had every form of convention
al therapy, including radical mastectomy,
post
operative
x-ray, hormone therapy,
as well as
oöphorectomy and adrenalectomy,
and they were
no longer responding to these forms of therapy.
The aim in this work has been to find out how sue
cessfully one can inhibit or destroy the pituitary
by this selective form of radiation as compared
with surgical hypophysectomy.
Figure 4 shows a
lateral view of the sella turcica in one of the pa
tients with the beam centered on the crosshair. It
is possible to cover most of the area occupied by
the pituitary within the sella with very little radia
tion being delivered to the surrounding tissues,
such as the hypothalamus and optic chiasm. Up to
the present time, use has not been made of the
Bragg curve, and the relatively great pituitary
dose is accomplished by continuous head rotation,
the beam being centered on the pituitary. There
are real problems encountered in avoiding irradia
tion of the vital structures surrounding the hy
pophysis, such as the optic tracts, the hypothala
mus, and the various cranial nerves. It has not
been possible to give as much radiation to this area
as one would like at the present time because of
Isotopes
in
the
Treatment
191
of Cancer
the danger of cranial nerve damage. However, al
ready in the first fourteen patients treated there is
evidence of marked pituitary suppression (Chart
7). Figure
5 shows
the
patient
in position
for treat
ment. Prior to irradiation the sella is very carefully
brought into position by taking x-ray photographs,
DEPTH IN CENTIMETERS
CHART
6.—Comparative
doses
at
surface
to
15 cm.
depth
for @OO
kv. x-rays, 16 mev electrons, and 190 mev deuterons
(which are like protons in depth effects).
and with the aid of crosshairs the beam is made to
fall on the exact center of the sella. During treat
ment the head is held tightly in a plastic mask and
continuously rotated through a 60°—70°
angle, 30°—
@‘—I3,85ORAD—j
@
(I)
I
zu) 50
>-o.@@:
@
v@::@T:::.
.
-T
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______________
CHART
treatment
7.—Patient
M.W.
.J,*,
Changes
in
v@!:*;r
pituitary
I
gonadotrophins,
I
P― uptake,
and
I
protein-bound
iodine
during
and
after
with 13,850 rads.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
Cancer Research
19@2
85°to the right and S0°—35°
to the left. The first pa
tient treated (Chart 7) was given 18,850 rads, one
r&d being roughly equivalent to a rep, delivered to
the pituitary over a period of about a month in
fractionated doses. As far as we know, the findings
in this case are the first clear-cut evidence that
target organ effects can be brought about by pitui
tary irradiation
(note decrease of pituitary gon
adotrophins and marked decrease in thyroid func
tion as shown by fall in I's' thyroid uptake, Chart
7).
@
@
Whether or not there will be a real application
of irradiation hypophysectomy,
or even surgical
hypophysectomy,
in cancer therapy is not yet
known. Another
or 8 years must elapse before
preliminary impressions regarding clinical benefits
in this series can be gained. Also, it will require an
other 5 years before it is known whether hypophy
sectomy will appreciably lengthen life in advanced
cancer of this or other types.
While I do not intend to belittle the achieve
ments of workers with artificial radioactivity
and
nuclear energy in cancer therapy, the results re
fiected in extension of life so far are not impressive.
However, when one must deal with the problem of
intractable pain, he learns to appreciate any pal
liative procedure which will make the patient more
comfortable even if significant extension of life is
not demonstrated.
Radioisotopes and the new ac
celerators and external sources of radiation have
given us tremendously
important new tools and,
from the humane standpoint,
have been a real
boon to cancer therapy. If a selectively localizing
compound
or compounds
can be found which
would emit a soft form of radiation, the really im
portant advances that could be realized are ob
vious. Much more basic research including that
with tracers is needed to learn more of the physiol
ogy of cancer. In the search for therapeutic bene
fits, our relative ignorance of the nature of neo
plastic growth is emphasized, and the solution to
the problem will probably not be found without
greater understanding
of the cancer process at the
cellular level.
ADDENDUM
At the International Conference on Peaceful Uses of Atomic
Energy held at Geneva in August, 1955, the author talked at
length to numerous Russian investigators
and learned that
during the past 3—Syears they have been very active in
Fio
1.—A scintogram
at various
times
after
applying the products of nuclear physics, especially isotopes,
to therapy, particularly in the use of 1131in Grave's disease, P―
in the treatment of polycythemia
vera and leukemia, and the
cobalt teletherapeutic units for external irradiation treatment
of cancer.
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
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•
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@T@?
.1....
I
I
I i
‘I
II
I
@
j@
1
,@ it
I
I
t
I HOUR
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II
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i
I
I
I
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
Fia. g.—A: Control animal with untreated mammary tu
mor; B: Healing tumor after bombardment with 190 mev
deuterons. The beam of deuterons was directed to the tumor
through the opposite side of the animal's body.
FIG. 8.—Four
radiation,
radiation
littermates
(left
to right):
producing
obesity; surgical
hypophysectomy;
control.
FIG. 4.—Diagnostic
hypothalamic
hypophysectomy;
x-ray of a patient's
head in position
ir
ir
for
treatment.
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can
is made by
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is enlarged by @0per cent owing to the finite focal distance of
the x-ray machine.
FIG. 5.—Patient
beam.
in position
for irradiation
with the proton
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
rC)
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1956 American Association for Cancer Research.
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Radioactive Isotopes and Nuclear Radiations in the Treatment
of Cancer
John H. Lawrence and Cornelius A. Tobias
Cancer Res 1956;16:185-193.
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