in the Treatment of Cancer Radioactive Isotopes and Nuclear by itlpw9937

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									                       Radioactive Isotopes and Nuclear Radiations
                               in the Treatment of Cancer*
                                          JOHN H. LAWRENCE AND CORNELIUS                              A. T0BIAs

                              (Donner Laboratory and Donner Pavilion,           University   of California,   Berkeley, Calif.)

    It is now @20ears since we began to use arti
                   y                                                             shipments is for medical use, and one-third of
ficially produced radioactive isotopes in cancer re                              these shipments are for cancer therapy. For in
search and in medical research. Actually, our first                               stance, there are 50 medical groups in the United
therapeutic trials were in 1936. In the early days                                States using radioactive colloidal gold and radio
the hope was that at the end of @0ears one could
                                          y                                      active colloidal chromic phosphate for interstitial
report outstanding examples of selective localiza                                 infiltration     in various types of cancer, such as
tion of radioactive compounds in neoplastic tissue,                              prostatic, uterine, and bronchogenic. Two hundred
making it possible to give the tumor tissue many                                 fifty groups are using radioactive gold, chromic
times more irradiation than the surrounding, nor                                 phosphate, and yttrium colloids in the treatment
mal tissues.                                                                     of cancer metastasized to the pleural and perito
    Up to the present moment, investigations with                                neal cavities. There are 400 groups using iodine
only two radioactive isotopes have given us impor                                181 in the diagnosis and treatment of hyperplastic
tant therapeutic applications in hyperplastic and                                and neoplastic thyroid disease and 889 groups
neoplastic diseases through selective localization.                              using         for
                                                                                             @32 the treatment of polycythemia vera
These are radiophosphorus          in the treatment   of                         and chronic leukemia. During 1954 there were
polycythemia      vera and radioiodine in the treat                              over 5,000 shipments of radioactive iodine from
 ment of the thyroid hyperplasia of Grave's disease                              Oak Ridge to individual users, over @,500ship
 and in the palliative treatment of certain thyroid                              Inents of radioactive phosphorus, and 6@ ship
cancers. However, one who has worked in the field                                 ments of radioactive gold. At the present time
from the beginning and who is asked to sum up his                                there are 30 cobalt teletherapy units in the United
experiences can't help saying that the therapeutic                               States in use for external irradiation therapy of
achievements have been disappointing;          but even                           cancer with high energy gamma rays, and 50 more
in the early days we believed that the greatest                                  are being planned (1).'
contribution     of radioactive isotopes in the field                                Most of the isotopes which have been used in
of medical and cancer research would lie in tracer                               the therapy of hyperplastic or neoplastic diseases
applications,    and we have devoted most of our                                 in the form of internal, intracavitary,    interstitial,
energies to the latter.                                                          contact, tele, or fission radiation are listed in
    Even though the achievements in prolongation                                 Chart 1 in the order of increasing atomic number.
of life and cures in cancer have not been great so                                   Early work by Kruger in this laboratory              15
far, one should not dismiss too lightly the con                                  years ago (@5) and by Zahl at al. (59), followed by
tributions    of artificial radioactivity   and nuclear                          the uranium fission experiments by Tobias at al.
radiations in cancer therapy. The clinician should                               (55), more recently has led to the trial of boron-lO
not underestimate        the importance of relief from                           in the treatment of brain tumors, particularly glio
pain and extension of comfortable life, and here                                 blastomas, the radiation being derived from the
their value is well established.                                                 fission of the boron nuclei after slow neutron cap
    The importance of the products of nuclear phys                               ture (7). Kruger bathed tumor slices in boric acid
 ics in cancer therapy is pointed up by the fact that                            solution in vitro and then irradiated them with
demands for radioactive isotopes in medical and                                  slow neutrons, causing fission of the boron nuclei
biological research have risen rapidly in the past 10                            into lithium and alpha particles. The ionization ob
years. The shipments of radioactive isotopes from                                tained is relatively densely localized, the particles
Oak Ridge National Laboratory have risen from                                    traveling about one cell diameter (55). After borax
less than 500 in 1946 to almost 1@,000 in 1954.                                  containing boron-lO was injected intravenously
 Seventy per cent of the total dollar value of all                               into patients with brain tumors who were then ex
                                                                                 posed to soft neutrons from the atomic pile, Farr,
   * Presented    as   part    of   the   Symposium   on   Radioactive   Iso
topes and    Cancer at the meeting of the American Association                   Sweet at al. (7, 13) have been able to deliver a few
of Cancer     Research in San Francisco, April 16, 1955. Papers                      ‘Atthe International Conference  @nthe Peaceful Uses of
presented    by David M. Greenberg and by Jacob Furth have                       Atomic Energy held in Geneva in August, 1955, the author
appeared    in the August, 1955, and the January, 1956, issues of                learned from Professors Modestov and Fateyeva that there are
Cancer Research, respectively.                                                   150 such units now in operation in the Soviet Union.
                                                                               185
    186                                                                  Cancer Research

    hundred roentgens to the tumor tissue by such fis                                           palliative treatment     of advanced cancer of the
    sion energy, but this is probably insufficient to give                                      bladder, but the survival time is not available for
    real therapeutic effect. Pathological studies of eight                                      a large series of patients (58). The beta- and gam
    of the first ten patients treated at Brookhaven                                             ma-emitting isotope Na24 has also been tried in the
    showed changes suggestive of irradiation effects in                                         treatment of chronic leukemia, but the method has
    three patients; however, large areas of viable tu                                           not found wide usage, since there is no selective
    mor were found in all cases (13). More recent in                                            localization of sodium.
    vestigations by Kruger have shown that the con                                                 The first example of a successful application of a
    centration of boron in the boundary between nor                                             radioactive isotope in therapy was the treatment
    mal and tumor tissue in glioblastoma multiforme                                             of polycythemia vera with @32•  Enough experience
    tumors in mice can be increased by injection of                                             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
                                                          carcinoma
                                                     ‘ian
@                                                         carcinoma, naso-pharynx tumor, maxillary tumor,
                                 I           I•.' esophaqeal carcinoma, uterine body carcinoma
                                 1 1                       carcinoma,
                                                 carcinomaDeep-seated cervix carcinoma, bronchogenic
                                    :...Prostate
                                                 —@Bladder tumors
                                                 carcinomaOvarian
                            carcinoma5r90Pterygium,
                                                             vernal conjunctivitis, vascularization of cornea
                                                 Hepatomegaly and splenomegaly in advanced leukemia
                 I      I            —      —       Thyroid         cancer         angina         pectoris                congestive           heart   failure.         hyperthyrodism

                                                        Hepatomegaly and splenomegaly in advanced leukemia
                             J   1                      Control of ascites and pleural effusion in metastatic carcinoma
      I                          I                      Prostate carcinoma, cervix carcinoma, bronchogenic carcinoma
       Other isotopes   used in therapy:                Calcium, Chromium, Gallium, Arsenic,                                                 Thulium, Lanthanum,                             Ceseum,
                                                        Astatine, Ruthenium
                                           CHART    1 .—Some    therapeutic          applications              of radioactive            isotopes


    Evans Blue dye containing boron-lO in the mole                                              to say that the condition can be satisfactorily con
    cule (@6). Although the localization of the radio                                           trolled by @82  (@9). The survival of patients with
    isotope achieved by use of the dye is 30 times that                                                                        is
                                                                                                polycythemia treated by @32 about equal to that
    obtained after injection of boron-lO as borax solu                                          in cases of pernicious anemia treated by liver or
    tion, the localization is greatest at the brain-tumor                                       vitamin B@2and diabetes mellitus treated by in
    interface and is not uniformly distributed through                                          sulin (Chart       a
                                                                                                                @), nd is superior to any increased
    out the tumor tissue. Consequently,       there is still                                    survival rate yet achieved in such cancers as
    insufficient localization in tumor cells to provide                                         breast or prostatic cancer with newer methods of
    the needed radiation. However, the use of such                                              therapy (Chart 3). The median survival in pa
    boron-containing     dyes should be explored. If fis                                        tients with polycythemia     vera is 14 years, com
    sionable material can be synthesized into com                                               pared with a survival of approximately     @0years for
    pounds that will give great selective localization in                                       an age-matched group of the general population.
    neoplastic tissue, there is little doubt that great                                         Since 1936, when         was
                                                                                                                      @32 first used in the treat
    therapeutic benefit can result.                                                             ment of chronic leukemia (30), thousands of pa
       Sodium-@4 and bromine-8@ have been used in                                               tients have been treated. As shown in Chart 3,
    the form of fluid instillation into the bladder for                                         approximately    50 per cent of the patients with
                 LAWRENCE                   AND      ToBrJ1s—Radioactive                  Isotopes    in   the   Treatment       of Cancer            187

chronic lymphatic leukemia treated by P@ will                                               is pipetted onto it, and the plaque is then applied
survive over 5 years (@8). This is somewhat better                                          directly to the lesion. In the case of basal-cell car
than the 8urvival in 1,600 cases treated by conven                                          cinoma, a dose of 34,000—36,000 rep is delivered to
tional methods reported in the literature review by                                                                           rep
                                                                                            the surface, and @0,000—@,500 delivered to the
Osgood (81).                                                                                first millimeter depth in a period of 48 hours. This
    Between 1985 and 1940, in the early days of the                                         method is producing results equal to those of any
radioisotope work, we attempted to treat a group                                            other of the more conventional methods now in use
of patients with breast cancer and prostate cancer                                          for the treatment of superficial skin cancer.
metastatic    to bone by means of intravenous      or                                           Radiophosphorus     as colloidal chromic phos
oral administration    of @32 Sr89 (@7, 80, 40). It
                              or                                                            phate (@1),first used by Jones et at. (fl), as well as
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        in
                   @32 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.



                                                                                                                               YEARS
                                                                                                CHART3.—Survival in cancer, leukemia, and polycythemia
 (0
                                                                                            compared with life expectancy in the general population (thin
 z                                                                                          line). For polycythemia   vera the dotted line represents the life
 >1                                                                                         expectancy after conventional forms of therapy (56) and the
 -j                                                                                         thick black line shows our results after treatmentwith P―(@9).
 z
 I—
 LU
                                                                                            For leukemia, the thick black line shows life expectancy in our
                                                                                            patients with chronic lymphatic leukemia treated with P―(Q8)
 LU
                                                                                            compared with average results in chronic myelogenous and
 0@                                                                                         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).
                                           YEARS
      CHART   L—The     survival       in polycythemia         vera   treated      with
 @32ompared
   c               with    the       survival   in diabetes       mellitus        treated
                                                                                                                             a
                                                                                            colloidal radiogold (p2,14, @4)nd radioyttrium,       is
with insulin and pernicious                 anemia     treated      with liver and          being currently given to patients suffering from
vitamin B-1Q.                                                                               pleural and ascitic effusions in metastatic        car
                                                                                            cinoma. This application of radioisotopes consti
   Friedell and associates have also made Sr9° p  a                                        tutes an important addition to palliative cancer
plicators for use in the treatment      of superficial                                      therapy. Although there is no evidence that such
tumors of the eyelids, conjunctiva,      and cornea!                                        therapy prolongs life, there is little question that it
ulcers (1@). The treatment of skin cancer and hy                                            relieves pain in many instances and slows down the
perkeratoses by @32    contact therapy (31) has added                                       accumulation of ascitic and pleural fluids, so that
another successful method for the treatment          of                                     paracentesis is often unnecessary or need be done
such lesions. Since 1943 Low-Beer has treated 350                                           at less frequent intervals.
hyperkeratoses by this method with a 5-year eradi                                               Colloidal chromic radiophosphate        and radio
cation rate of 98.8 per cent. Of the 190 basal-ce!!                                         gold are also being used interstitially for the treat
carcinomas treated, 97.6 per cent have been eradi                                           ment of carcinoma of the prostate before distant
cated for longer than 5 years. Also, 47 hemangio                                            metastases develop (8, 9, 46). The beta radiation
mas have been successfully treated by this meth                                             from these colloids allows a large tumor dose of
od. A small plaque of blotting paper is cut to fit the                                      radiation to be given without damage to surround
size of the lesion, the desired amount of Na2HP32O4                                         ing tissues, as might occur with conventional x-ray
188                                                Cancer Research

 therapy. Some workers point out the fact that                  good end results are reported (5, 34). In the
  chromic radiophosphate       has an advantage         over    case of thyroid cancer, however, it is rare that
  radiogold in that the former emits only beta rays,            radioiodine will localize sufficiently in a metastatic
  and less elaborate radiation protection measures              lesion to give a good therapeutic        result or cure,
  are needed. However, other workers believe that               even after complete thyroidectomy         or after a long
  radiogold gives a somewhat better therapeutic ef              course of propylthiouracil      or thyroid-stimulating
 feet because the greater penetration of the gamma              hormone (43). The cases in which there is a good
 radiation will, with the beta radiation, in effect             uptake of radioiodine, however, give one increas
 give a more uniform dose. Radioactive Y@ (@3)                  ing confidence that if selectively localizing corn
 and chromic phosphate (45) beads and radon im                  pounds can be found, lasting benefits might be
 plants (10) have been used for destruction of the              obtained     in advanced      cancer of other types
 pituitary in certain types of cancer. The tech                 also.
 nics for distributing radioactive materials in tis                Figure 1 is a gamma ray picture of the localiza
 sue may be improved in the future in some cases                tion of I's' in the body of a patient with thyroid
 by the intra-arterial    injection of the radioactive          rnetastases obtained in the first whole-body scan
 materials.                                                     ner now so widely used. This whole-body scintilla
     In 1948 we used colloidal chromic radiophos                tion scanner, developed by Anger and Tobias (8)
 phate in the treatment of a group of patients with            for photographing gamma ray-emitting isotopes in
 chronic leukemia, polycythemia         vera, and also a       the body, is shown in Chart 4. It consists of a series
 group with marked splenomegaly or hepatomegaly                of scintillation counters within lead cylinders. The
                                         We
 from miscellaneous causes (6, @). found these                 gamma ray energy from the isotope within the
 results no better than those following P@, as                 body is converted to light energy and photo
 Na@RP@O4, and, because of the chances of getting              graphed with a polaroid camera as the body is
the radiocolloid outside the vein with resultant               scanned. New methods for visualizing the distri
 radionecrosis, we have more or less abandoned the             bution of radioisotopes in vivo, such as the one de
 use of the various radiocolloids for the treatment            scribed here or the gamma ray pinhole camera
 of this group of diseases. Gofman and associates               (85), are expected to be of indirect use to therapy
used many other radiocolloids in the same group                through more accurate localization of tumors. The
 of diseases and arrived at the same conclusion (6).           patient illustrated in Figure 1 was a 68-year-old
     Cobalt-60 is being used in intracavitary       and in     male with thyroid metastases in the left upper
 terstitial therapy of nasopharyngeal and maxillary            arm, the chin, the sternum, the hip, the thigh, and
 tumors and uterine, prostatic, bladder, and bron              the ribs. Interestingly enough, two of these lesions
 chogenic carcinomas. In general, it is too early to           were not discernible by x-ray examination,              yet
evaluate the results in comparison with those                  they could be picked up by the scanner. This
achieved by conventional means of therapy. Hin                 method of locating tumors would of course have
man and co-workers (18, 47) treated 85 patients                important      diagnostic   applications    if localizing
with bladder tumors by intracavitary           irradiation     compounds emitting gamma rays could be found
using cobalt-60. They report that in four of nine              for other types of cancer. This particular patient
patients with tumor confined to the mucosa the                 had the largest uptake of radioactive iodine in
lesions were destroyed, but most infiltrating le               metastatic lesions that has come to our attention.
sions were only temporarily arrested.                          Comparative       counting rates over the tumor and
    The cobalt bomb teletherapeutic          units are of      an equal volume of normal tissue showed that the
wide interest now and are being used as substitutes            tumor concentration       of I's' was as much as @00
for @00    kv. x-ray equipment in the treatment of             times that in an equal volume of normal tissue.
deep-seated      tumors. Radiocobalt       provides the        During therapy with an oral dose of 100 mc. of
gamma ray source in these units, but other gamma               J131,   as   much   as   100,000   rep   in   radiation   was   deliv
ray emitters such as cesium are also being used,               ered to the neoplastic lesions. Prior to surgical
especially in Great Britain. These teletherapeutic             thyroidectomy    there was no uptake in these me
units have certain advantages over x-ray equip                 tastases. Now, 6 years later, this man is symptom
ment, such as cost and mobility, but one cannot                free, and, at the age of 74, he is an example of the
expect much improvement in end results over con                good result that can be obtained with isotope ther
ventional methods which use x-ray or other gam                 apy when there is a high selective uptake by neo
ma ray sources.                                                plastic tissue. Uptake in metastases can be stimu
    Since the first therapeutic      use of radioactive        lated by surgical thyroidectomy,     and administra
iodine (15, 16, 17, 80), it has been widely applied            tion of propy!thiouracil   and thyroid-stimulating
in the treatment      of hyperplastic thyroid disease          hormone are also sometimes helpful in increasing
or Grave's disease; indeed in many hospitals                   iodine uptake in metastases      (48). Another diffi
it is entirely replacing surgery, and remarkably               culty encountered in the treatment of metastatic
            LAWRENCE      AND T0BIAS—Radioactive            Isotopes    in   the   Treatment         of Cancer   189

thyroid cancer with radioiodine is that the radia            planted melanosarcoma. There was some localiza
tion dose may not be uniformly distributed in the            tion in the melanosarcomatous tissue, but there
tumor tissue. Surgery and x-ray continue to be the
primary tools for treating thyroid cancer.                                                             TYROS/NE
    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                                            4@O
                                                                           HOQI' —C--C—C—OH
ing tissues allow us to deliver relatively high doses                                             ii
of radiation to specific tissues. Perhaps in our                                                  H NH2
present state of relative ignorance regarding the
metabolic differences between the cancer cell and            was an appreciable uptake by the adrenal and
normal cell, it is too much to expect that a radio           thyroid glands, since tyrosine is a precursor of the
active compound can be found which will localize             hormones produced by these tissues.
 in cancer cells selectively enough to give V5, 50, or          The metabolism of stilbamidine containing C14
 more times the radiation than normal cells will             was studied in multiple myeloma, and, while it did




                       SCHEMATIC   DIAGRAM

                           CHART4.—Diagram of the scintillation   scanner (from Anger et at.)


receive. If such is to be found, the ideal isotopes to        localize in the myelomatous tissue, there was an
be built into the localizing compound would seem              even greater uptake by the liver.
to be hydrogen-S or carbon-14. The latter provide                These examples are typical of the many coin
relatively soft beta rays traveling only a few cell
diameters in tissue.                                                                               ST//JAM/DINE
   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
190                                                              Cancer Research

pounds that have been synthesized—localization                             astatic breast cancer by adrenalectomy            (@0).
of the radioactive compound is not sufficiently lim                          Olivecrona and associates were the first to report a
ited to the neoplastic cells to permit a good dose of                        remission in metastatic     breast cancer following
radiation to be given without damage to normal                               hypophysectomy      and have recently reported the
tissue.                                                                      results of this form of therapy in a series of 30 pa
    Some of the most interesting current investiga                           tients (8@2).Other workers in this field have esti
tions on selective localization are typified by the                          mated that approximately      50 per cent of patients
studies of Pressman and associates (41) . After im                           with advanced breast cancer have tumors which
munizing animals to various normal tissues and                               are hormone-dependent,     and approximately 50 per
neoplastic tissues and then adsorbing radioactive                            cent of the patients of this type undergoing sue
iodine to the antibodies, they have been able to                             cessful hypophysectomy      will show some evidence
demonstrate some localization of these antibodies                            of healing (38, 89). Apparently, the response is in
                                                                             dependent of the cellular type of mammary tumor,
                               •
                                Chronic lymphatic leukemia (131)             and whether the effect is always mediated through
                                Chronic myelogenousleukemia (138)            the ovaries and adrenals or whether there is a pri
                                Breast cancer, radical mastectomy
                               •
      0
                                   (125, Univ.of Rochester)                  mary pituitary factor is not yet known.
      z                         Stomach cancer (2772, Mayo Clinic
                               •
      >                         Lung cancer, pneurnonectomy
                                                                                With the hope that hypophysectomy        could be
      >                            (202, G.A Mason)                          achieved by irradiation, for 15 months we have
      U)                                                                     been making such attempts         using a somewhat
      I
      z
      w
                                                                             unique form of irradiation from the 184-inch cy
      C.)
                                                                                      3 This   work   is   a   projection   of   the   animal
      LU
      a.                                                                     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
                                     YEARS                                   with very little scatter, unlike a similar beam of
    CHART 5.—Survival rates in chronic lymphatic leukemia                  x-rays or gamma rays. Another unusual feature of
treated with P@ (@8), in breast cancer treated by radical                    these beams is that there is a relatively greater
mastectomy   (49), in stomach cancer treated by gastric resec                depth dose compared with surface dose. The com
tion (57), and lung cancer treated by pneumonectomy (33).                    parative doses at the surface and depth for @00v.    k
in the various normal and neoplastic tissues. More                           x-rays, 16 mev electrons, and 190 mev deuterons
recently Bale2 has achieved tumor localization of                            are given in Chart 6. The @00       kv. x-rays fall off
such antibodies 15 times greater than that of any                            markedly at 10-cm. depth, and the electrons from
normal tissue, indicating that this approach may                             the betatron or synchrotron also fall ofT consider
be a very hopeful one (4, 50).                                               ably, but the deuteron irradiation rises to a peak
   The therapy of cancer continues to be based                               at 14 cm., so that the depth dose is approximately
primarily on early diagnosis, surgery, and post                              4 times that entering at the surface.
operative x-ray therapy. Radioactive isotopes and                                Two animals with mammary cancer are shown
nuclear energy have not yet added importantly to                             in Figure @.  The one on the left is the control, and
the armamentarium        of cancer therapy, but the                          the one on the right has been irradiated by passing
relatively poor survival in cases of deep-seated                             the beam through the chest of the animal from the
cancer impels investigators       to make heroic at                          opposite side, localizing it on the tumor. In other
tempts to relieve these people and extend their                              words, it is possible to deliver energy in the depths
lives. As can be seen in Chart 5, the 50 per cent                            of tissues with relatively little skin effect using this
survival in the case of breast cancer, the most com                          form of radiation. Tobias et at. have applied this
mon type of cancer in women between the ages of                              beam to the pituitaries of rats, monkeys, and dogs
40 and 60, lung cancer, and stomach cancer is                                and have been able to remove the pituitary by this
approximately     8-5 years.                                                 selective form of external irradiation, producing
    One of the real advances in cancer therapy has                           atrophy of all the target organs, effects paralleling
been the revelation of the relation of hormones to                           those of surgical hypophysectomy.          Four litter
certain types of cancer, including the effects of                            mates are shown in Figure 8. The second from the
oophorectomy,      adrenalectomy,    and hypophysec                          left has had surgical hypophysectomy,          and the
tomy on advanced breast cancer (4@). Two ex                                  third from the left irradiation hypophysectomy.
amples in particular are the work of Huggins in the                          The animal on the left has been subjected to hypo
field of prostate cancer treated by orchiectomy and                          thalamic irradiation which produced obesity, and
diethyLstilbesterol (19), and the treatment of met                           the animal on the right is the control.
   * W.     F.   Bale,   personal    communication,         presented   at        @This work is supported by the Atomic Energy Commission,
“Atomsfor Peace Conferences,― Geneva,             August,   1955.        the California State Cancer Fund, and the Donner Foundation.
                      LAWRENCE                 AND       ToBJ.@&s—Radioactive                 Isotopes           in   the   Treatment                of Cancer                         191

        During the past year this beam has been applied                                         the danger of cranial nerve damage. However, al
    to the pituitaries of patients with advanced breast                                         ready in the first fourteen patients treated there is
    cancer and to two patients with leukemia, one hay                                           evidence of marked pituitary suppression (Chart
    ing an associated diabetes. This work has been the                                          7). Figure          5 shows         the   patient          in position          for treat
     subject of two previous reports which give much                                            ment. Prior to irradiation the sella is very carefully
     more detail (5@2,53). The patients with cancer                                             brought into position by taking x-ray photographs,
     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                                                                                  DEPTH IN CENTIMETERS
    dose is accomplished by continuous head rotation,                                                CHART    6.—Comparative              doses     at   surface     to     15 cm.   depth
    the beam being centered on the pituitary. There                                                     kv.
                                                                                                for @OO x-rays, 16 mev electrons, and 190 mev deuterons
    are real problems encountered in avoiding irradia                                           (which are like protons in depth effects).
    tion of the vital structures surrounding the hy
    pophysis, such as the optic tracts, the hypothala                                           and with the aid of crosshairs the beam is made to
    mus, and the various cranial nerves. It has not                                             fall on the exact center of the sella. During treat
    been possible to give as much radiation to this area                                        ment the head is held tightly in a plastic mask and
    as one would like at the present time because of                                                                                      angle,
                                                                                                continuously rotated through a 60°—70° 30°—
                                                                    RAD—j
                                                        @‘—I3,85O
@                        (I)          I                  v@::@T:::.                                           -T                                  T
                      zu) 50
                    >-o.@@:
@                                         .         .. •...c.•••••.                                                                               •.



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       CHART    7.—Patient   M.W.           Changes       in   pituitary    gonadotrophins,        P― uptake,       and       protein-bound            iodine    during      and    after
    treatment   with 13,850 rads.
    19@2                                                    Cancer Research

         t                        to the
    85°o the right and S0°—35° left. The first pa                        applying the products of nuclear physics, especially isotopes,
    tient treated (Chart 7) was given 18,850 rads, one                        to therapy, particularly in the use of 1131in Grave's disease, P―
                                                                              in the treatment of polycythemia    vera and leukemia, and the
    r&d being roughly equivalent to a rep, delivered to                       cobalt teletherapeutic units for external irradiation treatment
    the pituitary over a period of about a month in                           of cancer.
    fractionated doses. As far as we know, the findings                                                      REFERENCES
    in this case are the first clear-cut evidence that                                    P.
                                                                               1. AEBERSOLD, C. U.S. Atomic Energy Commission.Eight
    target organ effects can be brought about by pitui                              Year Summary of U.S. Isotope              Distribution.     Goveimment
    tary irradiation   (note decrease of pituitary gon                              Printing Office, 1955.
    adotrophins and marked decrease in thyroid func                              A
                                                                                @. NDREWS,          G. A.;     RoOT,     S. W.;    Knaai@i,     H.   D.;      and
                                                                                  B1GEWw, R. R. Intracavitary Colloidal Radiogold in the
    tion as shown by fall in I's' thyroid uptake, Chart
                                                                                  Treatment   of Effusion Caused by Malignant Neoplasm.
    7).                                                                           Ann. Surg., 137:375—81, 1953.
        Whether or not there will be a real application                        3. ANGER, H. 0. A Multiple Scintillation    Counter in Vivo@
    of irradiation hypophysectomy,         or even surgical                       Scanner. Am. J. Roentgenol.     Rad. Therapy & Nuclear
    hypophysectomy,      in cancer therapy is not yet                                               1953.
                                                                                    Med., 70:605—ig,
@                                                                              4.         W. F., and Sp@tn,I. L. In Vivo Localization of Rat
@   known. Another        or 8 years must elapse before                             Organ Antibodies in Ovaries, Adrenals, and Other Tissues.
    preliminary impressions regarding clinical benefits                                                    1954.
                                                                                    J. Immunol., 73:125—33,
    in this series can be gained. Also, it will require an                     5. CHAPMAN, E. M.; M@oop,                                   J.;
                                                                                                                            F.; M@is@ra@un@A, and
    other 5 years before it is known whether hypophy                                MARTiN,    J.   M.   Ten    Years'    Experience     with   Radioactive

    sectomy will appreciably lengthen life in advanced                            Iodide. J. Clan. Endocrinol. & Metabol., 14:45—55, 1954.
                                                                               6. DOBSON, E.; Knu@y, L. ; JONES, H. ; and Gorst@, J.
    cancer of this or other types.                                                  Radioactive Substances Specifically Localized in Liver,
        While I do not intend to belittle the achieve                             Spleen, or Bone Marrow, pp.                 XVII Interuat.
                                                                                                                       @6—@7.
    ments of workers with artificial radioactivity      and                       Physiol. Congress, Oxford, England, July, 1947.
    nuclear energy in cancer therapy, the results re                           7. F@a, L. E.; Swsmr, W. H.; ROBERTSON, J. S.; FOSTER,
                                                                                  C. G.; LOCESLEY,H. B.; Sum@i@n,          D. L.; MENDELSON,
    fiected in extension of life so far are not impressive.
                                                                                  M. L.; and STICKLEY, E. E. Neutron Capture Therapy
    However, when one must deal with the problem of                               with Boron in the Treatment of Glioblastoma Multiforme.
    intractable pain, he learns to appreciate any pal                             Am. J. Roentgenol.      Rad. Therapy      & Nuclear Med.,
    liative procedure which will make the patient more                            71:g79—91, 1954.
    comfortable even if significant extension of life is                       8. Fwcxs,R.H.;KmtR,H.D.;EixiNS,H.B.;andCuu',D.
                                                                                  Treatment    of Carcinoma of the Prostate by Interstitial
    not demonstrated.     Radioisotopes and the new ac                            Radiation   with Radioactive   Gold (Au198). J. Urol., 68:
    celerators and external sources of radiation have                               51o•-@.
    given us tremendously      important new tools and,                        9.          . Treatment of Carcinoma of the Prostate by Inter
    from the humane standpoint,          have been a real                         stitialRadiation   with Radioactive Gold (Au198): Follow-up
                                                                                  Report. Ibid., 71:6@8—SS,1954.
    boon to cancer therapy. If a selectively localizing
                                                                              10. FoRREST, A. P. M., and BROWN, D. A. Pituitary Radon
    compound      or compounds      can be found which                            Implant for Breast Cancer. Lancet, 268: 1054—55,1955.
    would emit a soft form of radiation, the really im                        11. FRIEDELL,H. L., and STORAASLI,J. P. The Use of Radio
    portant advances that could be realized are ob                                active Phosphorus in the Treatment of Carcinoma of the
    vious. Much more basic research including that                                Breast with Wide-spread       Metastases  to Bone. Am. J.
                                                                                  Roentgenol. & Rad Therapy, 46:559—75, 1950.
    with tracers is needed to learn more of the physiol
                                                                              1@. FRIEDELL, H. L.; THoseas,              C. I.; and KnoHirnt,        J. S. De
    ogy of cancer. In the search for therapeutic bene                               scription of an Sr9°Beta-Ray Applicator and Its Use on
    fits, our relative ignorance of the nature of neo                               the Eye. Am. J. Roentgenol. & Rad. Therapy, 65:@3@—44,
    plastic growth is emphasized, and the solution to                               1951.
    the problem will probably not be found without                            13. GODWIN, J. T.; F@uu1, L. E.; SWEET, W. H.; and ROBERT
                                                                                  SON, J. S. Pathological    Study of Eight Patients    with
    greater understanding     of the cancer process at the                        Glioblastoma    Multiforme  Treated by Neutron-Capture
    cellular level.                                                               Therapy Using Boron-lO. Cancer, 8:601—15, 1955.
                                                                              14. Goura, H., and ILtsIN, P. F. Distribution and Effect of
                           ADDENDUM                                               Colloidal Radioactive Gold in Peritoneal Fluid Containing
        At the International Conference on Peaceful Uses of Atomic                Free Sarcoma 87 Cells. Proc. Soc. Exper. Biol. & Med.,
    Energy held at Geneva in August, 1955, the author talked at                   74:634—38, 1950.
    length to numerous Russian investigators      and learned that            15. HAMILTON,J. G., and LAWRENCE,J. H. Recent Clinical
    during the past 3—Syears they have been very active in                      Developments in the Therapeutic Application of Radio




                                        Fio   1.—A scintogram      of a patient    with thyroid metastases
                                    at various   times   after    injection   of a tracer     dose of 1131. The
                                    scintillation scanner passes back and forth over the body,
                                    translating the gamma ray energy from the I's' within the body
                                    into light energy, which is then photographed with a Polaroid
                                    camera.
                                                                                    /
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                  I HOUR   48 HOURS                 96 HOURS
    I.
    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     littermates       (left   to right):     hypothalamic      ir
radiation,    producing   obesity; surgical             hypophysectomy;           ir
radiation    hypophysectomy;     control.
    FIG. 4.—Diagnostic      x-ray of a patient's            head in position   for
treatment.  The crosshairs mark the center of the beam. The
outlines of the sella turcica are clearly shown. The black spot
on the film on the left shows        the shape        of the beam,      which    can
be adjusted to fit each patient. The radioautograph                    is made by
briefly turning   on the proton      beam prior to developing             the film.
The beam spot is actual size, while the x-ray picture of the sella
                   p
is enlarged by @0er cent owing to the finite focal distance of
the x-ray machine.
   FIG. 5.—Patient       in position     for irradiation       with the proton
beam.
rC)
                          LAWRENCE                    AND            TornAs—Radioactive                        lsotopes        in      the     Treatment              of Cancer                            193

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