radioactive isotopes and nuclear radiations in the treatment of cancer* · infiltration in various...

in the Treatment of Cancer*

JOHN H. LAWRENCE AND CORNELIUS A. T0BIAs

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

shipments is for medical use, and one-third ofthese shipments are for cancer therapy. For instance, there are 50 medical groups in the UnitedStates using radioactive colloidal gold and radioactive colloidal chromic phosphate for interstitialinfiltration in various types of cancer, such asprostatic, uterine, and bronchogenic. Two hundredfifty groups are using radioactive gold, chromicphosphate, and yttrium colloids in the treatmentof cancer metastasized to the pleural and peritoneal cavities. There are 400 groups using iodine181 in the diagnosis and treatment of hyperplasticand neoplastic thyroid disease and 889 groupsusing @32for the treatment of polycythemia veraand chronic leukemia. During 1954 there wereover 5,000 shipments of radioactive iodine fromOak Ridge to individual users, over @,500shipInents of radioactive phosphorus, and 6@ shipments of radioactive gold. At the present timethere are 30 cobalt teletherapy units in the UnitedStates in use for external irradiation therapy ofcancer with high energy gamma rays, and 50 moreare being planned (1).'

Most of the isotopes which have been used inthe therapy of hyperplastic or neoplastic diseasesin the form of internal, intracavitary, interstitial,contact, tele, or fission radiation are listed inChart 1 in the order of increasing atomic number.

Early work by Kruger in this laboratory 15years ago (@5) and by Zahl at al. (59), followed bythe uranium fission experiments by Tobias at al.(55), more recently has led to the trial of boron-lOin the treatment of brain tumors, particularly glioblastomas, the radiation being derived from thefission of the boron nuclei after slow neutron capture (7). Kruger bathed tumor slices in boric acidsolution in vitro and then irradiated them withslow neutrons, causing fission of the boron nucleiinto lithium and alpha particles. The ionization obtained is relatively densely localized, the particlestraveling about one cell diameter (55). After boraxcontaining boron-lO was injected intravenouslyinto patients with brain tumors who were then exposed to soft neutrons from the atomic pile, Farr,Sweet at al. (7, 13) have been able to deliver a few

â€˜Atthe International Conference @nthe Peaceful Uses ofAtomic Energy held in Geneva in August, 1955, the authorlearned from Professors Modestov and Fateyeva that there are150 such units now in operation in the Soviet Union.

It is now @20years since we began to use artificially produced radioactive isotopes in cancer research and in medical research. Actually, our firsttherapeutic trials were in 1936. In the early daysthe hope was that at the end of @0years one couldreport outstanding examples of selective localization of radioactive compounds in neoplastic tissue,making it possible to give the tumor tissue manytimes more irradiation than the surrounding, normal tissues.

Up to the present moment, investigations withonly two radioactive isotopes have given us important therapeutic applications in hyperplastic andneoplastic diseases through selective localization.These are radiophosphorus in the treatment ofpolycythemia vera and radioiodine in the treatment of the thyroid hyperplasia of Grave's diseaseand in the palliative treatment of certain thyroidcancers. However, one who has worked in the fieldfrom the beginning and who is asked to sum up hisexperiences can't help saying that the therapeuticachievements have been disappointing; but evenin the early days we believed that the greatestcontribution of radioactive isotopes in the fieldof medical and cancer research would lie in tracerapplications, and we have devoted most of ourenergies to the latter.

Even though the achievements in prolongationof life and cures in cancer have not been great sofar, one should not dismiss too lightly the contributions of artificial radioactivity and nuclearradiations in cancer therapy. The clinician shouldnot underestimate the importance of relief frompain and extension of comfortable life, and heretheir value is well established.

The importance of the products of nuclear physics in cancer therapy is pointed up by the fact thatdemands for radioactive isotopes in medical andbiological research have risen rapidly in the past 10years. The shipments of radioactive isotopes fromOak Ridge National Laboratory have risen fromless than 500 in 1946 to almost 1@,000 in 1954.Seventy per cent of the total dollar value of all

* Presented as part of the Symposium on Radioactive Iso

topes and Cancer at the meeting of the American Associationof Cancer Research in San Francisco, April 16, 1955. Paperspresented by David M. Greenberg and by Jacob Furth haveappeared in the August, 1955, and the January, 1956, issues ofCancer Research, respectively.

185

Radioactive Isotopes and Nuclear Radiations

on March 8, 2021. © 1956 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

J 1

1 1:...Prostate

carcinoma, cervix carcinoma, bronchogeniccarcinomaDeep-seatedtumorsâ€”@Bladder

carcinomaOvariancarcinoma5r90Pterygium,

vernal conjunctivitis, vascularization of cornea

Cancer Research186

hundred roentgens to the tumor tissue by such fission energy, but this is probably insufficient to givereal therapeutic effect. Pathological studies of eightof the first ten patients treated at Brookhavenshowed changes suggestive of irradiation effects inthree patients; however, large areas of viable tumor were found in all cases (13). More recent investigations by Kruger have shown that the concentration of boron in the boundary between normal and tumor tissue in glioblastoma multiformetumors in mice can be increased by injection of

I I

palliative treatment of advanced cancer of thebladder, but the survival time is not available fora large series of patients (58). The beta- and gamma-emitting isotope Na24 has also been tried in thetreatment of chronic leukemia, but the method hasnot found wide usage, since there is no selectivelocalization of sodium.

The first example of a successful application of aradioactive isotope in therapy was the treatmentof polycythemia vera with @32â€¢Enough experiencehas been gained over the past @20years to allow one

SOME OF THE THERAPEUTIC USESOF RADIOACTIVE ISOTOPES

Glioblastoma multiformeBladder carcinomaPolycythemia, chronic leukemias, breast cancerControl of oscites and pleural effusion in metastatic

Deritoneal and aleural carcinoma.@ carcinoma, cervix carcinoma, bronchogenic carcinoma

erkeratosis, basal cell carcinoma, squamous cell carcinomaâ€˜iancarcinoma

@ carcinoma, naso-pharynx tumor, maxillary tumor,esophaqeal carcinoma, uterine body carcinomaI Iâ€¢.'

I IHepatomegaly and splenomegaly in advanced leukemia

â€” â€” Thyroid cancer angina pectoris congestive heart failure. hyperthyrodism

Hepatomegaly and splenomegaly in advanced leukemiaControl of ascites and pleural effusion in metastatic carcinomaProstate carcinoma, cervix carcinoma, bronchogenic carcinoma

Other isotopes used in therapy: Calcium, Chromium, Gallium, Arsenic, Thulium, Lanthanum, Ceseum,Astatine, Ruthenium

CHART 1 .â€”Some therapeutic applications of radioactive isotopes

Evans Blue dye containing boron-lO in the molecule (@6). Although the localization of the radioisotope achieved by use of the dye is 30 times thatobtained after injection of boron-lO as borax solution, the localization is greatest at the brain-tumorinterface and is not uniformly distributed throughout the tumor tissue. Consequently, there is stillinsufficient localization in tumor cells to providethe needed radiation. However, the use of suchboron-containing dyes should be explored. If fissionable material can be synthesized into compounds that will give great selective localization inneoplastic tissue, there is little doubt that greattherapeutic benefit can result.

Sodium-@4 and bromine-8@ have been used inthe form of fluid instillation into the bladder for

to say that the condition can be satisfactorily controlled by @82(@9). The survival of patients withpolycythemia treated by @32is about equal to thatin cases of pernicious anemia treated by liver orvitamin B@2and diabetes mellitus treated by insulin (Chart @),and is superior to any increasedsurvival rate yet achieved in such cancers asbreast or prostatic cancer with newer methods oftherapy (Chart 3). The median survival in patients with polycythemia vera is 14 years, compared with a survival of approximately @0years foran age-matched group of the general population.Since 1936, when @32was first used in the treatment of chronic leukemia (30), thousands of patients have been treated. As shown in Chart 3,approximately 50 per cent of the patients with



LAWRENCE AND ToBrJ1sâ€”Radioactive Isotopes in the Treatment of Cancer 187

chronic lymphatic leukemia treated by P@ willsurvive over 5 years (@8). This is somewhat betterthan the 8urvival in 1,600 cases treated by conventional methods reported in the literature review byOsgood (81).

Between 1985 and 1940, in the early days of theradioisotope work, we attempted to treat a groupof patients with breast cancer and prostate cancermetastatic to bone by means of intravenous ororal administration of @32or Sr89 (@7, 80, 40). Ithad been demonstrated that strontium, like calcium, localized to a high degree in bony tissue withless uptake than P@ in soft tissue. However, theresults were not exciting, and this work was abandoned when it became evident that it would beimpossible to deliver sufficient beta radiation tothe bony lesions without causing severe marrowdepression. Recently, Friedell (11) and others havere-introduced @32in this form of therapy andfound again that there is some relief of pain andoccasional evidence of healing. This type of therapy may have a small place in the palliation ofcancer metastatic to bone.

CHART Lâ€”The survival in polycythemia vera treated with

@32compared with the survival in diabetes mellitus treatedwith insulin and pernicious anemia treated with liver andvitamin B-1Q.

Friedell and associates have also made Sr9Â°applicators for use in the treatment of superficialtumors of the eyelids, conjunctiva, and cornea!ulcers (1@). The treatment of skin cancer and hyperkeratoses by @32contact therapy (31) has addedanother successful method for the treatment ofsuch lesions. Since 1943 Low-Beer has treated 350hyperkeratoses by this method with a 5-year eradication rate of 98.8 per cent. Of the 190 basal-ce!!carcinomas treated, 97.6 per cent have been eradicated for longer than 5 years. Also, 47 hemangiomas have been successfully treated by this method. A small plaque of blotting paper is cut to fit thesize of the lesion, the desired amount of Na2HP32O4

is pipetted onto it, and the plaque is then applieddirectly to the lesion. In the case of basal-cell carcinoma, a dose of 34,000â€”36,000 rep is delivered tothe surface, and @0,000â€”@,500rep delivered to thefirst millimeter depth in a period of 48 hours. Thismethod is producing results equal to those of anyother of the more conventional methods now in usefor the treatment of superficial skin cancer.

Radiophosphorus as colloidal chromic phosphate (@1),first used by Jones et at. (fl), as well as

CHART3.â€”Survival in cancer, leukemia, and polycythemiacompared with life expectancy in the general population (thinline). For polycythemia vera the dotted line represents the lifeexpectancy after conventional forms of therapy (56) and thethick black line shows our results after treatmentwith Pâ€•(@9).For leukemia, the thick black line shows life expectancy in ourpatients with chronic lymphatic leukemia treated with Pâ€•(Q8)compared with average results in chronic myelogenous andlymphatic leukemia reported in the literature (dotted line)(37). For breast cancer the increased survival achieved withradical mastectomy (thick black line) over that following nonradical procedures (dotted line) is shown (49). The survivalrate in cancer of the prostate following the Huggins method oforchiectomy and diethylstilbesterol (thick black line) is cornpared with survival prior to Huggins' work (dotted line) (36).

colloidal radiogold (p2,14, @4)and radioyttrium, isbeing currently given to patients suffering frompleural and ascitic effusions in metastatic carcinoma. This application of radioisotopes constitutes an important addition to palliative cancertherapy. Although there is no evidence that suchtherapy prolongs life, there is little question that itrelieves pain in many instances and slows down theaccumulation of ascitic and pleural fluids, so thatparacentesis is often unnecessary or need be doneat less frequent intervals.

Colloidal chromic radiophosphate and radiogold are also being used interstitially for the treatment of carcinoma of the prostate before distantmetastases develop (8, 9, 46). The beta radiationfrom these colloids allows a large tumor dose ofradiation to be given without damage to surrounding tissues, as might occur with conventional x-ray

YEARS

(0z>1-jIâ€”zLU

LU0@

YEARS



Cancer Research188

therapy. Some workers point out the fact thatchromic radiophosphate has an advantage overradiogold in that the former emits only beta rays,and less elaborate radiation protection measuresare needed. However, other workers believe thatradiogold gives a somewhat better therapeutic effeet because the greater penetration of the gammaradiation will, with the beta radiation, in effectgive a more uniform dose. Radioactive Y@ (@3)and chromic phosphate (45) beads and radon implants (10) have been used for destruction of thepituitary in certain types of cancer. The technics for distributing radioactive materials in tissue may be improved in the future in some casesby the intra-arterial injection of the radioactivematerials.

In 1948 we used colloidal chromic radiophosphate in the treatment of a group of patients withchronic leukemia, polycythemia vera, and also agroup with marked splenomegaly or hepatomegalyfrom miscellaneous causes (6, @).We found theseresults no better than those following P@, asNa@RP@O4, and, because of the chances of gettingthe radiocolloid outside the vein with resultantradionecrosis, we have more or less abandoned theuse of the various radiocolloids for the treatmentof this group of diseases. Gofman and associatesused many other radiocolloids in the same groupof diseases and arrived at the same conclusion (6).

Cobalt-60 is being used in intracavitary and interstitial therapy of nasopharyngeal and maxillarytumors and uterine, prostatic, bladder, and bronchogenic carcinomas. In general, it is too early toevaluate the results in comparison with thoseachieved by conventional means of therapy. Hinman and co-workers (18, 47) treated 85 patientswith bladder tumors by intracavitary irradiationusing cobalt-60. They report that in four of ninepatients with tumor confined to the mucosa thelesions were destroyed, but most infiltrating lesions were only temporarily arrested.

The cobalt bomb teletherapeutic units are ofwide interest now and are being used as substitutesfor @00kv. x-ray equipment in the treatment ofdeep-seated tumors. Radiocobalt provides thegamma ray source in these units, but other gammaray emitters such as cesium are also being used,especially in Great Britain. These teletherapeuticunits have certain advantages over x-ray equipment, such as cost and mobility, but one cannotexpect much improvement in end results over conventional methods which use x-ray or other gamma ray sources.

Since the first therapeutic use of radioactiveiodine (15, 16, 17, 80), it has been widely appliedin the treatment of hyperplastic thyroid diseaseor Grave's disease; indeed in many hospitalsit is entirely replacing surgery, and remarkably

good end results are reported (5, 34). In thecase of thyroid cancer, however, it is rare thatradioiodine will localize sufficiently in a metastaticlesion to give a good therapeutic result or cure,even after complete thyroidectomy or after a longcourse of propylthiouracil or thyroid-stimulatinghormone (43). The cases in which there is a gooduptake of radioiodine, however, give one increasing confidence that if selectively localizing cornpounds can be found, lasting benefits might beobtained in advanced cancer of other typesalso.

Figure 1 is a gamma ray picture of the localization of I's' in the body of a patient with thyroidrnetastases obtained in the first whole-body scanner now so widely used. This whole-body scintillation scanner, developed by Anger and Tobias (8)for photographing gamma ray-emitting isotopes inthe body, is shown in Chart 4. It consists of a seriesof scintillation counters within lead cylinders. Thegamma ray energy from the isotope within thebody is converted to light energy and photographed with a polaroid camera as the body isscanned. New methods for visualizing the distribution of radioisotopes in vivo, such as the one described here or the gamma ray pinhole camera(85), are expected to be of indirect use to therapythrough more accurate localization of tumors. Thepatient illustrated in Figure 1 was a 68-year-oldmale with thyroid metastases in the left upperarm, the chin, the sternum, the hip, the thigh, andthe ribs. Interestingly enough, two of these lesionswere not discernible by x-ray examination, yetthey could be picked up by the scanner. Thismethod of locating tumors would of course haveimportant diagnostic applications if localizingcompounds emitting gamma rays could be foundfor other types of cancer. This particular patienthad the largest uptake of radioactive iodine inmetastatic lesions that has come to our attention.Comparative counting rates over the tumor andan equal volume of normal tissue showed that thetumor concentration of I's' was as much as @00times that in an equal volume of normal tissue.During therapy with an oral dose of 100 mc. ofJ131, as much as 100,000 rep in radiation was deliv

ered to the neoplastic lesions. Prior to surgicalthyroidectomy there was no uptake in these metastases. Now, 6 years later, this man is symptomfree, and, at the age of 74, he is an example of thegood result that can be obtained with isotope therapy when there is a high selective uptake by neoplastic tissue. Uptake in metastases can be stimulated by surgical thyroidectomy, and administration of propy!thiouracil and thyroid-stimulatinghormone are also sometimes helpful in increasingiodine uptake in metastases (48). Another difficulty encountered in the treatment of metastatic



LAWRENCE AND T0BIASâ€”Radioactive Isotopes in the Treatment of Cancer 189

thyroid cancer with radioiodine is that the radiation dose may not be uniformly distributed in thetumor tissue. Surgery and x-ray continue to be theprimary tools for treating thyroid cancer.

The high selective localization of iodine in thyroid tissue and also the selective uptake of radiophosphorus by the bone marrow and blood-forming tissues allow us to deliver relatively high dosesof radiation to specific tissues. Perhaps in ourpresent state of relative ignorance regarding themetabolic differences between the cancer cell andnormal cell, it is too much to expect that a radioactive compound can be found which will localizein cancer cells selectively enough to give V5, 50, ormore times the radiation than normal cells will

planted melanosarcoma. There was some localization in the melanosarcomatous tissue, but there

TYROS/NE

SCHEMATIC DIAGRAM

CHART4.â€”Diagram of the scintillation scanner (from Anger et at.)

receive. If such is to be found, the ideal isotopes tobe built into the localizing compound would seemto be hydrogen-S or carbon-14. The latter providerelatively soft beta rays traveling only a few celldiameters in tissue.

Many workers have attempted to synthesizecompounds containing radioactive carbon andother radioelements for selective localization. Reidand Jones (44) made C'@-labeled tyrosine and injected some of it into animals carrying a trans

localize in the myelomatous tissue, there was aneven greater uptake by the liver.

These examples are typical of the many coin

ST//JAM/DINE

HOQI' 4@Oâ€”C--Câ€”Câ€”OH

iiH NH2

was an appreciable uptake by the adrenal andthyroid glands, since tyrosine is a precursor of thehormones produced by these tissues.

The metabolism of stilbamidine containing C14was studied in multiple myeloma, and, while it did



Cancer Research190

pounds that have been synthesizedâ€”localizationof the radioactive compound is not sufficiently limited to the neoplastic cells to permit a good dose ofradiation to be given without damage to normaltissue.

Some of the most interesting current investigations on selective localization are typified by thestudies of Pressman and associates (41) . After immunizing animals to various normal tissues andneoplastic tissues and then adsorbing radioactiveiodine to the antibodies, they have been able todemonstrate some localization of these antibodies

CHART 5.â€”Survival rates in chronic lymphatic leukemiatreated with P@ (@8), in breast cancer treated by radicalmastectomy (49), in stomach cancer treated by gastric resection (57), and lung cancer treated by pneumonectomy (33).

in the various normal and neoplastic tissues. Morerecently Bale2 has achieved tumor localization ofsuch antibodies 15 times greater than that of anynormal tissue, indicating that this approach maybe a very hopeful one (4, 50).

The therapy of cancer continues to be basedprimarily on early diagnosis, surgery, and postoperative x-ray therapy. Radioactive isotopes andnuclear energy have not yet added importantly tothe armamentarium of cancer therapy, but therelatively poor survival in cases of deep-seatedcancer impels investigators to make heroic attempts to relieve these people and extend theirlives. As can be seen in Chart 5, the 50 per centsurvival in the case of breast cancer, the most common type of cancer in women between the ages of40 and 60, lung cancer, and stomach cancer isapproximately 8-5 years.

One of the real advances in cancer therapy hasbeen the revelation of the relation of hormones tocertain types of cancer, including the effects ofoophorectomy, adrenalectomy, and hypophysectomy on advanced breast cancer (4@). Two examples in particular are the work of Huggins in thefield of prostate cancer treated by orchiectomy anddiethyLstilbesterol (19), and the treatment of met

* W. F. Bale, personal communication, presented at

â€œAtomsfor Peace Conferences,â€• Geneva, August, 1955.

astatic breast cancer by adrenalectomy (@0).Olivecrona and associates were the first to report aremission in metastatic breast cancer followinghypophysectomy and have recently reported theresults of this form of therapy in a series of 30 patients (8@2).Other workers in this field have estimated that approximately 50 per cent of patientswith advanced breast cancer have tumors whichare hormone-dependent, and approximately 50 percent of the patients of this type undergoing suecessful hypophysectomy will show some evidenceof healing (38, 89). Apparently, the response is independent of the cellular type of mammary tumor,and whether the effect is always mediated throughthe ovaries and adrenals or whether there is a primary pituitary factor is not yet known.

With the hope that hypophysectomy could beachieved by irradiation, for 15 months we havebeen making such attempts using a somewhatunique form of irradiation from the 184-inch cy

3 This work is a projection of the animal

studies of Tobias et at. (51, 54), who achieved hypophysectomy in the rat, dog, and monkey withbeams of high energy deuterons or protons. Oneunusual feature of the beam is its pencil-like naturewith very little scatter, unlike a similar beam ofx-rays or gamma rays. Another unusual feature ofthese beams is that there is a relatively greaterdepth dose compared with surface dose. The comparative doses at the surface and depth for @00kv.x-rays, 16 mev electrons, and 190 mev deuteronsare given in Chart 6. The @00kv. x-rays fall offmarkedly at 10-cm. depth, and the electrons fromthe betatron or synchrotron also fall ofT considerably, but the deuteron irradiation rises to a peakat 14 cm., so that the depth dose is approximately4 times that entering at the surface.

Two animals with mammary cancer are shownin Figure @.The one on the left is the control, andthe one on the right has been irradiated by passingthe beam through the chest of the animal from theopposite side, localizing it on the tumor. In otherwords, it is possible to deliver energy in the depthsof tissues with relatively little skin effect using thisform of radiation. Tobias et at. have applied thisbeam to the pituitaries of rats, monkeys, and dogsand have been able to remove the pituitary by thisselective form of external irradiation, producingatrophy of all the target organs, effects parallelingthose of surgical hypophysectomy. Four littermates are shown in Figure 8. The second from theleft has had surgical hypophysectomy, and thethird from the left irradiation hypophysectomy.The animal on the left has been subjected to hypothalamic irradiation which produced obesity, andthe animal on the right is the control.

@Thiswork is supported by the Atomic Energy Commission,the California State Cancer Fund, and the Donner Foundation.

â€¢Chronic lymphatic leukemia (131)Chronicmyelogenousleukemia (138)

â€¢Breast cancer, radical mastectomy(125, Univ.of Rochester)

â€¢Stomach cancer (2772, Mayo ClinicLung cancer, pneurnonectomy

(202, G.A Mason)

0z>>

U)

IzwC.)

LUa.

YEARS



(I) I v@::@T:::.@@ -T@ T

zu)>-o.@@:50@ . .. â€¢...c.â€¢â€¢â€¢â€¢â€¢. â€¢.

@tIk 60@@

______________ .J,*,@ v@!:*;r@@ I@ I I

LAWRENCE AND ToBJ.@&sâ€”Radioactive Isotopes in the Treatment of Cancer 191

During the past year this beam has been appliedto the pituitaries of patients with advanced breastcancer and to two patients with leukemia, one haying an associated diabetes. This work has been thesubject of two previous reports which give muchmore detail (5@2,53). The patients with cancerhave previously had every form of conventional therapy, including radical mastectomy, postoperative x-ray, hormone therapy, as well asoÃ¶phorectomy and adrenalectomy, and they wereno longer responding to these forms of therapy.The aim in this work has been to find out how suecessfully one can inhibit or destroy the pituitaryby this selective form of radiation as comparedwith surgical hypophysectomy. Figure 4 shows alateral view of the sella turcica in one of the patients with the beam centered on the crosshair. Itis possible to cover most of the area occupied bythe pituitary within the sella with very little radiation being delivered to the surrounding tissues,such as the hypothalamus and optic chiasm. Up tothe present time, use has not been made of theBragg curve, and the relatively great pituitarydose is accomplished by continuous head rotation,the beam being centered on the pituitary. Thereare real problems encountered in avoiding irradiation of the vital structures surrounding the hypophysis, such as the optic tracts, the hypothalamus, and the various cranial nerves. It has notbeen possible to give as much radiation to this areaas one would like at the present time because of

@â€˜â€”I3,85ORADâ€”j

the danger of cranial nerve damage. However, already in the first fourteen patients treated there isevidence of marked pituitary suppression (Chart7). Figure 5 shows the patient in position for treat

ment. Prior to irradiation the sella is very carefullybrought into position by taking x-ray photographs,

CHART 6.â€”Comparative doses at surface to 15 cm. depth

for @OOkv. 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 tofall on the exact center of the sella. During treatment the head is held tightly in a plastic mask andcontinuously rotated through a 60Â°â€”70Â°angle, 30Â°â€”

DEPTH IN CENTIMETERS

CHART 7.â€”Patient M.W. Changes in pituitary gonadotrophins, Pâ€• uptake, and protein-bound iodine during and after

treatment with 13,850 rads.



19@2 Cancer Research

85Â°to the right and S0Â°â€”35Â°to the left. The first patient treated (Chart 7) was given 18,850 rads, oner&d being roughly equivalent to a rep, delivered tothe pituitary over a period of about a month infractionated doses. As far as we know, the findingsin this case are the first clear-cut evidence thattarget organ effects can be brought about by pituitary irradiation (note decrease of pituitary gonadotrophins and marked decrease in thyroid function as shown by fall in I's' thyroid uptake, Chart7).

Whether or not there will be a real applicationof irradiation hypophysectomy, or even surgicalhypophysectomy, in cancer therapy is not yetknown. Another@ or 8 years must elapse beforepreliminary impressions regarding clinical benefitsin this series can be gained. Also, it will require another 5 years before it is known whether hypophysectomy will appreciably lengthen life in advancedcancer of this or other types.

While I do not intend to belittle the achievements of workers with artificial radioactivity andnuclear energy in cancer therapy, the results refiected in extension of life so far are not impressive.However, when one must deal with the problem ofintractable pain, he learns to appreciate any palliative procedure which will make the patient morecomfortable even if significant extension of life isnot demonstrated. Radioisotopes and the new accelerators and external sources of radiation havegiven us tremendously important new tools and,from the humane standpoint, have been a realboon to cancer therapy. If a selectively localizingcompound or compounds can be found whichwould emit a soft form of radiation, the really important advances that could be realized are obvious. Much more basic research including thatwith tracers is needed to learn more of the physiology of cancer. In the search for therapeutic benefits, our relative ignorance of the nature of neoplastic growth is emphasized, and the solution tothe problem will probably not be found withoutgreater understanding of the cancer process at thecellular level.

ADDENDUM

At the International Conference on Peaceful Uses of AtomicEnergy held at Geneva in August, 1955, the author talked atlength to numerous Russian investigators and learned thatduring the past 3â€”Syears they have been very active in

applying the products of nuclear physics, especially isotopes,to therapy, particularly in the use of 1131in Grave's disease, Pâ€•in the treatment of polycythemia vera and leukemia, and thecobalt teletherapeutic units for external irradiation treatmentof cancer.

REFERENCES1. AEBERSOLD,P. C. U.S. Atomic Energy Commission.Eight

Year Summary of U.S. Isotope Distribution. GoveimmentPrinting Office, 1955.

@.ANDREWS, G. A.; RoOT, S. W.; Knaai@i, H. D.; andB1GEWw, R. R. Intracavitary Colloidal Radiogold in theTreatment of Effusion Caused by Malignant Neoplasm.Ann. Surg., 137:375â€”81, 1953.

3. ANGER, H. 0. A Multiple Scintillation Counter in Vivo@Scanner. Am. J. Roentgenol. Rad. Therapy & NuclearMed., 70:605â€”ig,1953.

4.@ W. F., and Sp@tn,I. L. In Vivo Localization of RatOrgan Antibodies in Ovaries, Adrenals, and Other Tissues.J. Immunol., 73:125â€”33,1954.

5. CHAPMAN, E. M.; M@oop, F.; M@is@ra@un@A,J.; andMARTiN, J. M. Ten Years' Experience with Radioactive

Iodide. J. Clan. Endocrinol. & Metabol., 14:45â€”55, 1954.6. DOBSON, E.; Knu@y, L. ; JONES, H. ; and Gorst@, J.

Radioactive Substances Specifically Localized in Liver,Spleen, or Bone Marrow, pp. @6â€”@7.XVII Interuat.Physiol. Congress, Oxford, England, July, 1947.

7. F@a, L. E.; Swsmr, W. H.; ROBERTSON, J. S.; FOSTER,C. G.; LOCESLEY,H. B.; Sum@i@n, D. L.; MENDELSON,M. L.; and STICKLEY,E. E. Neutron Capture Therapywith Boron in the Treatment of Glioblastoma Multiforme.Am. J. Roentgenol. Rad. Therapy & Nuclear Med.,71:g79â€”91, 1954.

8. Fwcxs,R.H.;KmtR,H.D.;EixiNS,H.B.;andCuu',D.Treatment of Carcinoma of the Prostate by InterstitialRadiation with Radioactive Gold (Au198). J. Urol., 68:51oâ€¢-@.

9. . Treatment of Carcinoma of the Prostate by InterstitialRadiation with Radioactive Gold (Au198): Follow-upReport. Ibid., 71:6@8â€”SS,1954.

10. FoRREST, A. P. M., and BROWN, D. A. Pituitary RadonImplant for Breast Cancer. Lancet, 268: 1054â€”55,1955.

11. FRIEDELL,H. L., and STORAASLI,J. P. The Use of Radioactive Phosphorus in the Treatment of Carcinoma of theBreast with Wide-spread Metastases to Bone. Am. J.Roentgenol. & Rad Therapy, 46:559â€”75, 1950.

1@. FRIEDELL, H. L.; THoseas, C. I.; and KnoHirnt, J. S. Description of an Sr9Â°Beta-Ray Applicator and Its Use onthe Eye. Am. J. Roentgenol. & Rad. Therapy, 65:@3@â€”44,1951.

13. GODWIN, J. T.; F@uu1, L. E.; SWEET, W. H.; and ROBERTSON, J. S. Pathological Study of Eight Patients withGlioblastoma Multiforme Treated by Neutron-CaptureTherapy Using Boron-lO. Cancer, 8:601â€”15, 1955.

14. Goura, H., and ILtsIN, P. F. Distribution and Effect ofColloidal Radioactive Gold in Peritoneal Fluid ContainingFree Sarcoma 87 Cells. Proc. Soc. Exper. Biol. & Med.,74:634â€”38, 1950.

15. HAMILTON,J. G., and LAWRENCE,J. H. Recent ClinicalDevelopments in the Therapeutic Application of Radio

Fio 1.â€”A scintogram of a patient with thyroid metastasesat various times after injection of a tracer dose of 1131. Thescintillation scanner passes back and forth over the body,translating the gamma ray energy from the I's' within the bodyinto light energy, which is then photographed with a Polaroidcamera.



/

I

I/I'..'

o@0 ii

I I

% It Iâ€˜I

I i

- â€¢-- -@=-@-

â€¢ â€¢â€¢=-=@

â€¢@

//

@T@?.1....

I.

â€˜I

III j@

1@,@ it

I I I II I III I

I iI I

t I

96 HOURSI HOUR 48 HOURS



Fia. g.â€”A: Control animal with untreated mammary tumor; B: Healing tumor after bombardment with 190 mevdeuterons. The beam of deuterons was directed to the tumorthrough the opposite side of the animal's body.

FIG. 8.â€”Four littermates (left to right): hypothalamic irradiation, producing obesity; surgical hypophysectomy; irradiation hypophysectomy; control.

FIG. 4.â€”Diagnostic x-ray of a patient's head in position fortreatment. The crosshairs mark the center of the beam. Theoutlines of the sella turcica are clearly shown. The black spoton the film on the left shows the shape of the beam, which canbe adjusted to fit each patient. The radioautograph is made bybriefly turning on the proton beam prior to developing the film.The beam spot is actual size, while the x-ray picture of the sellais enlarged by @0per cent owing to the finite focal distance ofthe x-ray machine.

FIG. 5.â€”Patient in position for irradiation with the protonbeam.



rC)



LAWRENCE AND TornAsâ€”Radioactive lsotopes in the Treatment of Cancer 193

Phosphorus and Radio-Iodine. J. Clin. Investigation, 21:6@4,1942.

16. HAMIIJTON, J. G., and Soi@ziy, M. H. Studies in IodineMetabolism by the Use of a New Radioactive Isotope ofIodine. Am. J. Physiol., 127:567â€”72, 1939.

17. Huni'z, S., and ROBERTS, A. Application of RadioactiveIodine in Therapy of Grave's Disease. J. Clin. Investigation, 21:624, 1942.

18. HzNuaN, F., Ja.; SCHULTE, J. W.; and LOW-BEER, B. V. A.Further Experience with Intracavitary Radiocobalt forBladder Tumors. J. Urol., 73:285â€”91,1955.

19. lluoonis, C. Prostatic Cancer Treated by Orchiectomy.The Five-Year Results. J.A.M.A., 131:579-81, 1946.

@0.Huoan@s, C., and DAO, T. L-Y. Adrenalectomy in Treatment of Advanced Carcinoma of the Breast. J.A.M.A.,151:1388â€”94,1953.

21. JAFFII, H. L. Treatment of Malignant Serous Effusionswith Radioactive Colloidal Chromic Phosphate. Am. J.Roentgenol. Rad. Therapy & Nuclear Med., 74:657-66,1955.

@. Joiras, H. B.; WROBEL, C. G.; and LYONS, W. R. A Meth

od of Distributing Beta-Radiation to the Reticulo-endothelial System and Adjacent Tissues. J. Clin. Investigation, 23:783â€”88, 1944.

@23.KENNEDY,T. ; RASMUSSEN,T., and H@uu'zu,P. V. TheUseofa Beta-Ray Source forDestruction of the Hypophysis. Siug. Forum, 4:681â€”86, 1958.

@24.KiNG, E. R.; Spzczia, D. W.; DOWDA,F. W.; BENDrn,M. A.; and NOEL, W. E. The Use of Radioactive Gold(Au1N) in Pleural Effusions and Ascites Associated withMalignancy. Am. J. Roentgenol. Had. Therapy & NuclearMed., 68:416â€”20, 1952.

25. KRUGER, P. G. Some Biological Effects of Nuclear Disintegration Products on Neoplastic Tissue. Proc. Nat.Acad. Sc., 26:181â€”92,1940.

26. . Boron Uptake in Mouse-Brain Neoplasms. Radiation Research, 3:1â€”17,1955.

@7.Lawunrwsi, J. H. Observations on the Nature and Treatmeat of Leukemia and Allied Diseases. Proc. Inst. Med.Chicago, 14:30-49, 1942.

@8. . The Treatment of Chronic Leukemia. Med.Clinics N. America, 38:525-40,1954.

29. â€”. Polycythemia Vera: Physiology, Diagnosis, andTreatment, pp. 69â€”70.New York: Grune & Stratton, 1955.

80. L&wum@cE, I. H.; IhssiLTON, J G.; Ear, L. A.; andPECHER, C. Recent Advances in Clinical Medicine with theAid of Artifically Prepared Radioactive Isotopes. J. Cliii.Investigation, 20:436, 1941.

81. Low-B@a, B. V. A. The Therapeutic Use of RadioactiveIsotopes, GP, pp. 69â€”87.1954.

32. Lurr, R., and OL1VECRONA,H. Hypophysectomy in Man.Experiences in Metastatic Cancer of the Breast. Cancer,8:261â€”70,1955.

83. MASON,G. A. Cancer of the Lung: Review of 1,000 Cases.Lanoet, 2:587â€”90, 1949.

34. McCuiiaoii, E. P. Radioactive Iodine in the Treatmentof Hyperthyroidism. Ann. mt. Med., 37:739â€”44,1952.

35. Mois'rnsiiu, R. K.; ANGER, H 0.; and T0BIAS, C. A. TheGamma-Ray Pinhole Camera and Image Amplifier. Univ.of Calif. Radiation Lab. Report 2524, 1954.

36. NESBrr, R. M., and BAtm&,W. C. Endocrine Control ofProstatic Carcinoma. J.A.M.A., 143:1317â€”20,1950.

37. Osooor, E. E., and Snass@&N,A. J. Treatment of ChronicLeukemias. J.A.M.A., 150:1372â€”79, 1952.

38. PEARSON,0. H.; RAY, B. S.; HAluIou, C. C.; WEST, C. D.;Li, M. C.; MACLEAN, J. P.; and LIPSETr, M. B. Hypophysectomy in the Treatment of Advanced Cancer. Trans.Am. Assoc.Phys. (inpress).

39. PEARSoN,0. H.; WEST, C. D.; H0LI.ANDER,V. P.; and

â€˜fREVES, N. E. Evaluation of Endocrine Therapy for Ad

vanced Breast Cancer. J.A.MA., 154:234-39,1954.40. PECHER, C. Biological Investigations with Radioactive

Calcium and Strontium. Proc. Soc. Exper. Biol. & Med.,46:86â€”91, 1941.

41. Punseaw@, D. Antibodies as Specific Chemical Reagents.In: J. H. Lawrence and C. A. Tobias (eds.), Advances inBiological and Medical Physics, 3:99â€”152.New York:Academic Press, 1953.

42. RAWSON,R. W. Hormonal Control of Neoplastic Growth.Bull. New York Acad. Med., 29:595â€”611, 1953.

43. RAWSON,R. W. ; Rai,L, J. E. ; and ROBBINS,J. Uses andMisuses of Radioactive Iodine in Treatment of Cancer ofThyroid. A.M.A. Arch. Int. Med., 92:299-807, 1958.

44. RaiD, J. C., and JONES,H. B. Radioactivity Distributionin the Tissues of Mice Bearing Melanosarcoma after Administration of DL-Tyrosine Labeled with RadioactiveCarbon. J. Biol. Chem., 174:427â€”37, 1948.

45. ROTBENBERG,S F.; [email protected], H L.; Pum@us,T. J.; andSIMK.IN, B. Hypophysectomy with Radioactive Chromic

Phosphate in Treatment of Cancer. A.M.A. Arch. Neurol.& Psychiat., 73:193â€”99, 1955.

46. RTJSCEE,C., and Jai@t, H. L. The Treatment of ProstaticCarcinoma with Radioactive Colloidal Chromic Phosphate(i@E) Trans. Am. Assoc. Genito-urinary Surgeons, pp.48â€”56,1953.

47. SCEULTE,J. W.; Hiintair, J., JR.; and LoW-B@, B. V. A.Radiocobalt for Treatment of Bladder Tumor. J. Urol.,67:916â€”24,1952.

48. Sumur@r,S. M.; Rossatar', I.; OSERY,E.; and SIEGEL,E.Radioiodine Therapy of Metastases from Carcinoma of theThyroid: a Six-Year Progress Report. J. Clin. EndocrinoL,9:1122â€”37,1949.

49. Satau@, R. G., and DtrrroN, A. M. Survival of Patientswith Cancer of the Breast.J.A.M.A.,157:216â€”19,1955.

50. Sp@ii, I. L., and@ W. F. In Vivo Localization of Labeled Rat Adrenal Antibodies. J. Iminunol., 73:134-37,1954.

51. T0BIAS, C. A.; Airoun, H. 0.; and LAWRENCE, J. H.Radiological Use of High Energy Deuterons and AlphaParticles. Am. J. Roentgenol. Rad. Therapy & NuclearMed., 67:1â€”27,1952.

52. T0BIAS, C. A.; ROBERTS,J. E.; L@wumic@, J. H.; LowBumi, B. V. A.; ANGER,H. 0.; Bousi,J. L.; McCoums,R.;and Huosin@s, C. Radiation Hypophysectomy with HighEnergy Proton Beams. Univ. of Calif. Radiation Lab.Report 3035, 1955

58. . Pituitary Irradiation with High-Energy ProtonBeams: A Preliminary Report. Cancer (in press).

54. TOBIAS, C. A.; Vaii Dm@, D. C.; SiupsoN, M E.; ANGER,H. 0.; Hurr, R. L.; and Ko@iw, A. A. Irradiation of thePituitary of the Rat with High Energy Deuterons. Am J.Roentgunol. Red. Therapy & Nuclear Med., 72:1â€”fl,1954.

55. T0BIAS,C. A.; WEYMOUTU,P. P.; and WAssmuwi, L. R.Some Biological Effects Due to Nuclear Fission. Science,107:115-18, 1948.

56. VIDEBARK,A. Polycythemia Veraâ€”Courseand Prognosis.Acta Med. Scandinav., 138:179â€”87,1950.

57. WALTERS,W.; GEAY,H. K.; and Paizsmzv, J. T. Carcinoma and Other Malignant Lesions of the Stomach.Philadelphia: W. B. Saunders, 1942.

58. WALTON, R. J., and Sz@ci.@uR,W. K. Radioactive Solu.tions (24Na and EBr) in the Treatment of Carcinoma of theBladder. Brit. Med. Bull., 8:158â€”65, 1952.

59. ZAHL, P. A.;Coopun, F. S.;and DUNNnW, J.R. Some i*Vivo Effects of Localized Nuclear Disintegration Productson a TransplantableMouse Sarcoma. Proc.Nat. Acad.Sc., 26:589, 1940.



1956;16:185-193. Cancer Res John H. Lawrence and Cornelius A. Tobias of CancerRadioactive Isotopes and Nuclear Radiations in the Treatment

Updated version

http://cancerres.aacrjournals.org/content/16/3/185.citation

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/16/3/185.citationTo request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



radioactive isotopes and nuclear radiations in the treatment of cancer* · infiltration in various...

Documents