Advances in Cancer Research

TlrF; JoUH.'.fAL OF'

l'.1-to 1·,()(!Y

Vo!.. s:1, -'Jo . 5, I\Jay 1\JGO Prin.led 1·r1 f) ..~'<.i.l,

ADV~L\CES E\ CANCER RESEARCH JOH'.\ TL HELLER firorn the National Cance, In.s/.itul.e, National Institutes of Health, Pubhc Health .8cn·1ce, Derwrlnu;nl 0 1

H1m/th 1 Education and TYelfa.re, Bethesda, Mr/.

in the excel-

J am JJ!'i vilcgc
this meeting. We are

an eminent member of Uw impcirtant branch of in which many in thi1,; audience are

He was indeed a stal\\'art honor fur me to have been w give the: Rol,ert l\fomorial

to discus,, ad n1uccs in cancer resr,,arcI, has 111e a mosf, welcome oppor-tunity to take stoek, were--to reflect on the ~tatu~ of this

of medical re-· no doubt will sonw uut Urn means for the ultimate eonof maligna.nt ,hscases but :Llso reveal some of tl1c secrets of life itself. of thP It sccrns to n-w that n true situation depends on the ress is rneasttrcd :whi.1,ven1euts m two separnk and at the same tirne interdependent comof ca 11crr n:,ean:h: rr n-,scnrr:h has come of age. oi began at the close, of the nineteenth centur~- with the of ,111inrnl tumors arnl of these

turn om into nmv lw:c;ts. 13ut l O to years has then' been nn accclrm1.tion in tempo and a surge of

<1 tlw resouref-:S avail8blc have prncl11ced a pattern a v1goruus, the products

lll

advances yet to he achieved. tl,e status uf cancer some of the

Western Section. Inc., l\I 011tercy: F:r.litm s note.

that arc available for th8 research l'ffnrt. Acc1)r,J , J shall describe first some of tlie of progress m ancl a few of the mon: n·c,,ut of research on a type of ca.m·<-'r uf cern to this audienc<-·. l slinll cmwludc of the rxtent of cancer iu t.hl' l · uit.cd States and the of th<: dlort that h:if h(·•,n to combat iL \/Jh.OLOG:Y 1'ir?<8C8. For mo1·c tli,n, y,,ai·s evidencP that vin1sc,s cause uu11:c:1· 111 animals has been accnmulating. The last dee:,, lias brought to light some i11fornrnt1nr, about animal tumor viruses and about t.he furnhmcntal. natun' of viruses ancl cell con1pom,n As a, result, canec:r stRte of knowledge ,md HH, arc. now ad nn1 c·c,cl intensified effort on the problem viral etiology of human cancer. Table l shows some uf the in virus-cancer researeb. After Borre! in 190:3 t.fmt Yiruses cause c:ancl·r, n·,w:ixc.h in tliis area proceeded mt.her significance of the n'sults 1n1s nut nized, In 1908, Ellenn,u1 :me! the first direct ca1isal rc,lationship bet1H:en cancer and a vims in tlwir work 011 the mission of fowl ]eukemi:t cl'lJ-fn·(· Soon after, in HJIJ, Hou~ disco1Tred tlu1t sarcoma. tlrnt ap}.Jt:ared Rock <·hicb'D could be pasSi'cl chickc:n to d1icken means of cell-frc:e fiJlr:"tk0c, Almost a quarter of a <:entury before next advances were n,c:onJed: the cowry of the, Shope pnpillmn:i. ,,irus in IK\:3. the· Lucke virus of tlw leopard rn and th, Bittner mammary tumor \'irus of mi<:<, in l The: <:ontcmpornry period of inten~1fied n,,ean]; on cancer viruses might be con.siclt'red as from Gross' observations in H):'il tliat the 11\\wu Jation of nr:wborn mice ,l"it,h c:rll-free r xtr:1d.-. 1

Lccturn. rn director of the

Stanley, W Relationships, establishn) prospective, bc:tween virnses and ,,,.,,,c,,r. N.Y. Acad. Sci . 71: J 100-111:3, 1\15S. 1

National Cauccr 515

516

JOHN R. HELLER TABLE

1. Virus-cancer research, 1903-1936

1903-Borrel, first suggested viruses cause cancer 1908-Ellerman and Bang\ discovered animal 1911-Rous f virus tumors 1933-Shope, solid tumor in rabbits 1934-Lucke, kidney cancer in frogs 1936-Bittner, breast cancer in mice obtained from mouse leukemia tissue resulted in leukemia within one or two years (table 2). National Institutes of Health investigators Stewart and Eddy, working with some of Gross' material, observed that the mice developed parotid-gland tumors. 2 When these investigators subsequently carried cell suspensions of bits of parotid-gland tumors in tissue culture, the tumorproducing capacity of the material took an explosive course. Injection of supernatant fluid from the cultures into newborn mice resulted in the development of 23 different types of primary tumors, including parotid-gland tumors, and tumors of the thymus, adrenal glands, and mammary glands. Stewart and Eddy showed subsequently that this agent, now known as the polyoma virus, has the additional remarkable capacity of crossing strain and species barriers. It induces sarcomas and vascular tumors in hamsters, and renal sarcomas and subcutaneous tumors in rats. 3 • 4 It is believed that the material with which Gross was working contained two viruses, the leukemia virus and the parotid-gland tumor virus, and that the activity of the latter is increased by passage through tissue culture. Suddenly, it appears as if a catalyst is at work speeding discoveries of tumor viruses. Friend, working at the Sloan-Kettering Institute for Cancer Research, reported the discovery of a virus that induced leukemia in mice of any age within as short a period as two or three weeks after inoculation. 5 This agent was found during 2 Stewart, S. E., Eddy, B. E. and Borgese, N.: Neoplasms in mice inoculated with a tumor agent carried in tissue culture. J. Nat. Cancer Inst., 20: 1223-1243, 1958. 3 Eddy, B. E., Stewart, S. E., Young, R. and Mider, G. B.: Neoplasms in hamsters induced by mouse tumor agent passed in tissue culture. J. Nat. Cancer Inst., 20: 747-761, 1958. 4 Eddy, B. E., Stewart, S. E., Stanton, M. P. and Marcotte, J.M.: Induction of tumors in rats by tissue-culture preparations of SE polyoma virus. J. Nat. Cancer Inst., 22: 161-171, 1959. 5 Friend, C.: Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia. J. Exp. Med., 105: 307-318, 1957.

TABLE

2. Virus-cancer research, 1951-1959

1951-Gross, leukemia in mice 1956-Stewart and Eddy, multiple tumors in mice, rats, and hamsters 1957-Friend, leukemia in mice 1957-Friend, immunized mice against leukemia 1957-Burmester, immunized chickens against visceral lymphomatosis 1957-Schwartz, enhanced mouse leukemia by injection of human leukemia tissue 1957-Dmochowski, observed virus particles in human leukemia tissue 1958-Stewart and Eddy, immunized hamsters against polyoma virus 1959-Moloney, leukemia in mice studies on the effect of cell-free preparations of the Ehrlich ascites tumor in infant Swiss mice. Just a few weeks ago Moloney at the National Cancer Institute reported that he had isolated from sarcoma 37, a transplantable tumor of mice, a virus that produces lymphocytic neoplasms in mice. 6 The activity of the virus has been increased so that it now produces leukemia within 10 weeks in all mice injected on the first day of life. Virus-like particles have been seen in leukemic cells examined under the electron microscope. In contrast to other leukemogenic viruses affecting mice, the virus elicits the disease in several different strains, is active in adults as well as newborns, and produces a leukemia indistinguishable from the spontaneous type of the disease. Still another investigation that appears to involve viruses has been reported recently. Investigators at the National Cancer Institute observed about two years ago that several mouse plasma cell tumors are strikingly similar to human multiple myeloma in microscopic appearance of tissues, development of bone lesions, and production of an abnormal blood serum protein. Studies of the fine structure of six plasma cell tumors under the electron microscope revealed a significant characteristic common to all the tumors: the presence of virus-like particles in various stages of formation within the tumor cells. 7 There is no indication that these particles 6 Moloney, J. B.: Preliminary studies on a mouse lymphoid leukemia virus extracted from sarcoma 37. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 44, 1959. 7 Dalton, A. J. and Potter, M.: Some of the features of the fine structure of a series of plasma cell tumors of mice. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 14, 1959.

ADYA,,TCES IN CANCER RESEARCH

:are associated with the of the mouse tumors. However, Ittrtlwr studies will include ,efforts to determine ,vhether viruses are involved in causation of the mouse plasma cell neoplasms .and to extend the results to investigations of human multiple research on anirnal tumor viruses progresses, attempts are made to develop vaccines that will protect ornce,,n~+; animals against the tumors. Stewart and successfullv inhibited the development of tumors induced hamsters the polyoma virus. The procedure involved young hamster, with a "neutral" mixture of polyorna ,·irus and antibodv-containing rabbit scrum. Hamsters were i1{jected with the virus-antibody mixture when two davs ·old a.nd again six days later. On challenge with the active virus alone tlni weeks after the second immunizing injection, H7 per cent of the hamsters failed to develop turnor~ aud survived six months until the was terminated. Sixtvseven per cent of thP trnimrnunized control litt;r .mates that received the same virus challenge died with tumors witbin five months. Development of a vacciue that was effective in protecting mice against the type of leukemia the Friend virus has been reportecP The a formalin-killed virus preparation, \Vas given in a series of three injections at weekly intervals. When ""'"''""'cu with live virus, about 80 per eent of tlw rrnimals proved to be immune to the disease. As yet, no evidence has been produced to show that any form of human cancer is caused by ,, virus. However, in the past few years manv new human viruses which ha\'t: not yc:t bee~ corr~lated with diseases have been foun2L A great deal of new information has been obtained about the intricate nature of tissue culture tech-niques, chemical similarities of viruses and cell components that are carriers of heredity (table 3). Furthermore, virus particles have been seen in electron micrngraphs of human leukemic tissues. 10 If a synthesis of knowledge produced

i;1

Stewart, S. E. and Eddy, B. K: Tumor inducby polyoma virus and the inhibition of tumors specific neutralizing antibodies. Presented at Pub. Health Assoc. meeting. St. Louis Mo Oct. 28, 1958.. . . ., 9 Friend, C.: Immunological studies on a filterable agent causing a leukemia-like disease in mice. (Abstract.) Proc. Am. Assoe. Cancer Res. 2: 204 1957. '. ' 10 Dmochowski, L. and associates: Studies on human leukemia. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 17, 1959. • 8

t.10H

TA.BLE

3. A-ids to virus-cancer nsw.rch H anciling Vfruses

l9IO~Carrel and 1910-- Volpino

B

'i first. urrowsf .1

growth <)f cells in tiss1w

ture

Uncie/'8la:nchng the Nature of V1:n1scs

1927-Busch, tfovelopment, of the. electron nucru.

scope 1939--Stanley 1951-Zinder and Lederberg 1956-Fraenkel-Conrat 1956--Gierer and Schramm

of

chemistry

and

ology of virnse,

by studies sucb as these sr10ukl yield cone:lusi I e evidence for the presence of viruses in cancer, and if viruses should be established caltsative agents, a truly rern,trkable milestom, will have been achieved. The K ational Cancer Institute is porting a program designed to stimulate on the relationship of viruses to lmrnnn cancer both in intra.mum.I activities and extramurnl facilities through the grants program. YVi1,hin the, past 2 months, nearly ,$1 million in g;rnntb been awarded to about a dozen gators, several of whom ar0 eminent whose talents will now be focused on whether cancer is a virus disease. A st.wt rnade with tissue culture and electron ""'"~""···-· studies of material derived from humnn sources. Later, the mech,rnisms of immune rcspmrnes. the relationships between reRistance or bility to infection and to cancer, the "''"''"".h,,c of blood serum, and the characteristics of 11.m1 gen-antibody systems, all relatively areas, will be investigated. These will be range studies, and the results will he slow H, coming, but our expectations are high that th,c accomplishments will be significant. Viral of ca.ncer. Th; finding n. fow ago that adenoviruses had a ""'Ja '''"·''""'we effect on the HeLa cell suggested that these viruses might have some effect on similar ceUR iu humar, beings. HeLa cells are cancer cells that have been kept alive in tissue culture since 19,5 I, when were removed from a patient who had carcinomn of the cervix. Injection of adenoviruses into cervical cancer ma.ss or into the bloodstream in ,1 small group of patients resulted in the tion and disappearance of most of the cancerous mass." However, all the cancer cells were no( u Smith, R. R. and associates: Studies on L!Se of viruses in the treatment of carcinoma of the cervix. Cancer, 9: 1211-1218, 1956.

518

JOHN R. HELLER

destroyed by the time neutralizing antibodies to the virus developed, and these served to protect the residual cancer. The fact that infection of cancer cells with viruses causes the destruction of the cancer cells is most significant. Further research in this area involves attempts to adapt other human viruses by means of known passage techniques to become oncolytic against human tumors and also to alter the host reaction to a virus to permit complete oncolysis. Such studies are in progress at the National Cancer Institute and elsewhere. CHEMOTHERAPY

Chemotherapy is one of the most active areas in cancer research today, primarily because investigators have become convinced that drugs will ultimately provide the means for effective treatment of disseminated cancer. The research is proceeding simultaneously along several lines, such as, for example, development of new classes of drugs, alteration of the structure of drugs already known to possess some anticancer activity, and improvement in techniques for administering known drugs. A few examples will serve to illustrate the diversity of these investigations. One of the drugs recently developed is 5fluorouracil (5-FU), a member of a new class of antimetabolites known as fluorinated pyrimidines. Antimetabolites, you will recall, are believed to accomplish their anticancer action by blocking an essential sequence of events in the biosynthesis of a vital cell component, nucleic acid. The cell is deprived of an essential element, and the end result is the death of the cell following disruption of its metabolism. Methotrexate, a folic acid antagonist, and 6mercaptopurine, a purine antagonist, are wellknown examples of antimetabolites; 5-FU is a pyrimidine antagonist. Reports have been published on the results of several clinical studies, in which 5-FU has been tested in some 350 patients according to a treatment schedule developed by Curreri and his colleagues. 12- 15 A rather broad spectrum of solid Curreri, A. R. and associates: Clinical studies with 5-flourouracil. Cancer Res., 18: 478-484, 1958. 13 Curreri, A. R.: Further clinical studies with 5-flourouracil. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 14, 1959. 14 Brennan, M. J. and Vaitkevicius, V. K.: 5-Fluorouracil alone and with 6-mercaptopurine in the clinical therapy of solid tumors. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 9, 1959. 15 Sullivan, R. D .. Miller, E., Murphy, V. D. 12

tumors responded to the drug when it was given until stomatitis or moderate diarrhea appeared. Objective remissions were observed in patients with cancer of the breast, colon and rectum, cervix, ovary, and liver. Conversely, malignant lesions of the lung, stomach, and pancreas and malignant melanoma were unaffected by this compound. 5-Fluorouracil appeared to be contraindicated in patients who had received prior extensive radiotherapy or leukopenia-producing doses of alkylating agents, because such patients were especially vulnerable to severe hematopoietic depression. Attempts to reduce the toxicity of 5-FU led to the preparation of a derivative, 5-fluoro-2' deoxyuridine (5-FUDR). Patients receiving this drug tolerated almost twice as much 5-FUDR as 5-FU before signs of toxicity appeared. 16 Evaluation of the anticancer properties of the drug are still in progress. A new drug developed by alteration of the structure of one now in clinical use is 3', 5'dichloroamethopterin, which was derived from the antileukemia drug, methotrexate. The compound has been placed recently in preliminary clinical trial under the program of the Cancer Chemotherapy National Service Center and results of its anticancer effects are not yet available. However, it is interesting to review some of the laboratory studies to clarify the reason for our interest in this compound and, at the same time, illustrate the type of research that precedes the clinical research stage in the development of drugs. Laboratory studies at the National Cancer Institute had previously shown that methotrexate was more effective against advanced mouse leukemia than a number of other drugs, including 6-mercaptopurine, thioguanine, and 8-azaguanine. 17 The comparison was made by a procedure, especially developed to assay new chemotherapeutic agents, in which mice were injected with leukemia and then treated with the test drug starting about the seventh day. At this and Mechanic, R.: The value of 5-flourouracil in human cancer. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 68, 1959. 16 Ansfield, F. J.: Toxicity and preliminary clinical studies with 5-fluoro-2' -deoxyuridine (5-FUDR). (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 3, 1959. 17 Goldin, A. and associates: Quantitative evaluation of chemotherapeutic agents against advanced leukemia in mice. J. Nat. Cancer Inst., 21: 495-511, 1958.

i\DVANCES I;;f CANCEH RESEARCH

TREATMENT OF ADVANCED LEUKEMIA (L 1210) /6)

1

/6)

100

\18)

/8)

90 If> >,

I

80

0

0

w

70

~

I-

60

....J

~

i

<[

> >

~ I

a::

so~

::)

40

(/)

t t

Amethopterin

/4) (4) (2)

l

N12)

/o! -

I

z

<(

0

w ::;;;

3' 8romo-5'chloroamethopterin

IOc=-------------+-----CONTROLS-----+--------------·--= ~Treatment from day

7to90

I

0 ~----~--'---..f--_l____ LI

048

0.75

118

1.84

171

_j__

267

_ j_ __J___

41.8

65.3

_j__ _

102

L_--+_

160

_L_

__l_ _J__

171

26.7

41.8

_j___

65.3

_J_ __L___ _

102

160

DAILY DOSE mg./kg, F1G. 1. Treatment of 11dvanctcd mouse leukemia (L-1210) with rnethoi,rexai,c l11mtl)rin) :ind 111•0 ol its clilrnlogenated derivatives. :VIedian survival time obtairl()d trning IO mice show11 at crnch level ,,J daily treatment for tmch agen1,. :viedia.11 survival times in excess of 100 d11ys :ue indicn.teci b)· nrT11W;< pointing npwardtJ. Figun,s in parentheses are nurnber of IOO-da\· survivor,, in various exp1)rinwnt11.l g.:roupt:L

time thl' disease was and untreated animals dice! within t,\·o to three· da>·s. \Vhen tested by this procedure, control mice died in about 10 wlH rcaF those receiving rnethotn·xatc had a median survival time of about 30 when treated front 7. As sbown in figmC' 1, under similar conditions, mice n·c<)iving :3', i?-dicbloroamcthopterin and another dc1in1ti vc, :3'-hrorno-.5'-dtloroamethopkrin, had a mcdim1 survival time of more than 13 In one JOO on day 100, 41 survivors remained out of 130 mice treated at various dosage levels of the dichloro compouncl and 42 rema.i1wd ont of another group of 130 mice treated with the bromo-chloro compound. Some of the animals \\'ere still :.din° at the encl of six "cunxl." \Vhile clo not guarantee similar re~ults in provide an 0

"c:o!din, A. a.nc! :1ssociates: Prolongation of 1hc iifespan of mice \Vith advanced -leukemia ( !, 1210) by treatment "·iih halogenated deriva tiv(,s of umeihoplcrin . .J. Nut. Cancc-r Inst., 22: Sll-82:l. Jll50.

experimental demonstration of ol controlling lcuke1nia 1\ttempts hav<) IH't,n made to 1rH'n'a,e tlw anticancer cffrdin·m·ss and reduc(,: the l;oc:I. of another well-known mustarcl. A derivative that appears is cyclophosplmmidc (l\i, X N', 0-propylene-phosplwric acid ester diami, ll·), whitl1 was clrveloped in Cc:rm:1 uy Hild tested throngh the facilitic::, o[ th,) Cancer Clwrnotlicrapy National ~crviec C,,nter. Jn clinical stnclirs, the cornponnd sl1mY<'
R.avdin, R G.

S. H. · Clinical s(mlies (Abstract.) Proc Am. Assoc. Hl,50.

520

JOHN R. HELLER

metastases was demonstrated. Furthermore, good subjective response, particularly of bone pain, occurred in a number of cases. A third example of the effort to improve existing drugs is in the area of the steroids. 2-Alphamethyl dihydrotestosterone propionate, a derivative of testosterone propionate developed in Mexico, was tested in a small group of postmenopausal women with metastatic breast cancer. 20 The results reported by Blackburn and his associates were as follows: 12 of 27 patients given the new drug experienced temporary regression of metastatic lesions, as compared with 3 of 21 patients given testosterone propionate. The new derivative thus appears to exert an inhibitory effect at least equal and possibly superior to that of testosterone, and androgenic effects significantly less potent than those produced by testosterone. Definitive evaluation of the usefulness of 2-alpha-methyl dihydrotestosterone propionate awaits further clinical experience. The drug has not been used in patients with cancer of the prostate, but probably will be scheduled for clinical trial in due course. An exciting advance in treatment of a rare but highly malignant tumor has been reported by National Cancer Institute scientists through the use of a specially designed regimen for administering methotrexate. 21 Some 40 women patients with the malignant solid tumor, choriocarcinoma, have been treated at the National Cancer Institute during a period of about three years. Most of them were gravely ill on admission, with widespread involvement of the pelvic region and metastases to the lungs. A few also presented evidence of central nervous system metastases. The drug was given intramuscularly or by continuous intravenous drip in a large dose administered in equal portions over a period of five days. The course was repeated at about twoweek intervals for two months or more. Response to treatment was measured by the amount of the hormone, chorionic gonadotrophin, produced by the tumor and excreted in the urine. Other responses observed were chest x-ray changes and improvement in pelvic and cerebral involvement. 20 Blackburn, C. M. and Childs, D. S., Jr.: Use of 2 alpha-methyl androstan-17-beta-ol, 3-one (2-methyl dihydrotestosterone) in the treatment of advanced cancer of the breast. Proc. Staff Meet. Mayo Clinic, 34: 113-126, 1959. 21 Hertz, R. and associates: Chemotherapy of choriocarcinoma and related trophoblastic tumors in women. J. A. M.A., 168: 845-853, 1958.

Complete remissions with no hormonal, radiologic, or physical evidence of recurrence for periods ranging from several months to three years have been observed in about one-third of the patients. One patient has been free of the disease for 36 months, without any signs of the malignancy or of increased gonadotrophin titer. One-third of the patients have been clinically free of the disease, but show chemical evidence of activity of the tumor; and one-third have responded either only initially or not at all. The success in prolonging the lives of even this small group of patients is extremely encouraging, when one considers that this tumor usually kills a patient in less than one year. In a recent study reported by Li and his colleagues, working at the Sloan-Kettering Institute for Cancer Research, several patients with metastatic testicular choriocarcinoma, which has not previously responded to methotrexate, and one with methotrexate-resistant uterine choriocarcinoma showed normal urinary chorionic gonadotrophin titers and regression of pulmonary metastases for periods of 1 to 7 months when treated with a combination of drugs. 22 These included actinomycin-D plus an alkylating agent (chlorambucil, diepoxypiperazine, or nitrogen mustard) either alone or in combination with methotrexate or the antibiotic, DON (6-diazo5-oxo-L-norleucine). The adjuvant use of chemotherapy with surgical treatment represents another effort to improve the effectiveness of drugs presently in clinical use. 23 Surgical excision of the gross tumor is followed by chemotherapy for the residual cells. This procedure is based on the results of laboratory experiments suggesting that an agent moderately effective against an advanced tumor may be curative against smaller tumors and unestablished tumor cells. Several statistically designed clinical studies have recently been organized in this area under the auspices of the Cancer Chemotherapy National Service Center, using nitrogen mustard in patients with resectable cancer of the lung, chlorambucil in cancer of the ovary, and thio-TEPA (triethylene thiophosphoramide) in cancer of the stomach, colon, 22 Li, M. C., Whitmore, W. and Colbey, R.: Effect of combined drug therapy upon metastatic choriocarcinoma. (Abstract.) Proc. Am. Assoc. Cancer Res., 3: 37, 1959. 23 Shimkin, M. S. and Moore, G. E.: Adjuvant use of chemotherapy in the surgical treatment of cancer. J. A. M.A., 167: 1710--1714, 1958.

ADVANCES IN CAXCEH RESK\HCH

and rectum. Survival among tbese patients will be compared with survival among patients rece1vmg identical treatment except for the adjuvant material Isolation-perfusion techniques in which a localized area. is perfused with a drug are being developed also as an adjunct to surgery. One study recently rcportr.d described encouraging patients with reclinical response shown gionally confined maligna.nt melanoma.2 4 Perfusion of the involved extremity with thio-TEPA was followed by wide local excision of the primary lesion and removal of regional nodes where appropriate. Of 15 patients with metastatic melanoma of a lower 13 showed disappearance or and clinical research remains to be done to arrive at an understanding of the varinblcs involved in the perfusion of a localized area ancl the optimum conditions for uptake of the drug by the tumor. Chemotherapy research in the United States and England, in particular, has produced about 20 agents thaL are now in standard use. These compounds are useful temporarily m aJJeyiating symptoms and m many cases prolonging the useful life of suffering from about 15 types of cancer, including leukemia, Hodgkin's disease, and advanced cancers of the breast and prostate gland. The compounds in elude adrenal steroids and antimetaboalkylating radioactive isotopes and hormonal altcrants. The majority of these were some of them developed within the last LJ,rc nitrogen mustard, methotrexate, aminoptcrin, 6-mercaptopmine, mylcran, chlorambucil, and thio-TEPA. The research aetivities have been accelera.kd in the last several years as a result of the national cancer chemotherapy progra,m of research, rstablished by the l:nited States Government to discover and evaluate compounds for the treatment of cancer. The program is directed the Cancer Chemotherapy .National Service Center, which has the responsibility of irnplemcntmg, co-ordinating, and directchemotherapy research ing voluntary nn m-,m,nT in laboratories and hospitals throughout the United States and abroad. The Service Center which is located at the National Cancer Insti2 ' Krementz, E. T, and ,i,ssociates: The isolationperfnsion treatment of human cancer. (Abstract.) Proc. Am. l\_ssoc. Cnncer Res. 3: :34, 19.59.

tute, is sponsored jointly by the National CnncFr Institute, Veterans Administration, Food /l.nd Drug Administration, Atomic Energy Comrni,; sion, and two non-Federal agencit,s, the Amcric:i,n Cancer Society and Damon Runyon "\Iemor·i:d Funn for Cancer Research (fig. 2). The program embraces three major the acquisition and initial screening for cancer activity of many thousands of chemical compounds a year, further testing of compounds in larger animals and in the labnnt" tory to develop safe doses for human trial;,, and evaluation in extensive clinical trial,,. A.bout 40,000 materials a year arc scn·<'m'cl. large number of these are "off the shelf" nm!,, rials---steroids, synthetic chcmieals, and biotic bcers--but an incrl'asing proportion compounds that han° been m clw laboratory on the basis of the theory tha, been developrd on the nwchanism of action nl' anticancer drugs. Some !00 drugs, includ steroids, alkylating agents, antinwt:1bolit,·~, and antibiotics, have come through all the of testing and arc now iu clinical. triab in -1-,'lllil patients. About 20 per cent of the drugs have hcrt· in use sevc,ral years and are being us('d as encc compounds with which the m:\\Tr are compared. Seventeen co-opemtin: study group~ of 6 to 12 investigators each, representing I hospital services throughout the United Statl'·>, have been formed to evaluate pokutial cancer drugs in clinical trials. Tlw 1Yeskn, group is studying leukemia., lyrnplwm:1. 1 multiple rnycloma. Oth('r Western participants iu some of the groups ,stud? the treatment of cancern of and the, use of drugs as adjtmds to smgcry CYTOLOGY

Cytology, another promising research, is providing information not immediate importance to the practicing cian in detecting cancer, hut also of' significance in contributing to bctkr 1mderst:rnc1ing of tbe nature of cancer. For example, the possibility has breu rc,:ognized that cancer cells may cireubtt: in t!w peripheral blood of individuals for some Linic before nwtastasis occurs. But the lack uf quan titative methods for detecting nmlignant ,·ells blood has hampered efforts to r:ontirrn thi,,.

522

JOHN R. HELLER

AMERICAN CANCER SOCIETY

FOOD ANO DRUG ADMINISTRATION

DAMON RUNYON MEMORIAL FUND INDUSTRY SUBCOMMITTEE

ATOMIC ENERGY COMMISSION

VETERANS AOMI NI ST RATION CANCER CHEMOTHERAPY NATIONAL SERVICE CENTER

CHE MISTRY

PANEL

ORUG EVALUATION

PANEL

l

ENDOCRINOLOGY PANEL

Fm. 2. Cancer chemotherapy integrated program which is guided by Cancer Chemotherapy National Committee. An Industry Subcommittee advises on industrial activity. Program is directed by Cancer Chemotherapy National Service Center at National Cancer Institute, Bethesda, Md. hypothesis and to apply the findings in further studies of metastasis and diagnostic tests. Malmgren and others at the National Cancer Institute have now reported the development of a quantitative technique for preparing human whole blood so that it can be examined cytologically.26 Preparation of the blood for microscopic examination involves the removal of erythrocytes and certain white blood cells without altering or removing tumor cells. The process requires two hours from the time the blood is collected until it is ready for examination. Approximately 20 minutes is required for screening each slide. In tests of the technique of samples of whole blood to which had been added a known number of tumor cells obtained from a variety of sources, the margin of error was less than 10 per cent and the tumor cells remained morphologically intact. Use of the technique for the examination of peripheral blood obtained from a vein in the antecubital fossa of 100 patients with a diagnosis of cancer and 200 presumably well people with no evidence of cancer and no history of the disease revealed that cytologically malignant 25 Malmgren, R. A. and associates: A method for the cytologic detection of tumor cells in whole blood. J. Nat. Cancer Inst., 20: 1203-1213, 1958.

cells were identified in 39 per cent of the cancer patients and suspicious cells were present in an additional 12 per cent. 26 In the control group, on the other hand, cells that were considered to be malignant were found in 1 person, or 0.5 per cent. This person has since been found to have a very small carcinoma of the lung. As shown in table 4, the relation of type of lesion to the presence or absence of malignant cells was not clear cut. Malignant squamous cells appeared to exfoliate into the blood at least as often as cells from adenocarcinomas. Sarcomas exfoliated cells into the blood with about the same regularity as carcinomas. Other studies in cytology have been done with the cytologic technique evolved by Papanicolaou and Traut for detecting malignant cells in fluids taken from natural body orifices. 27 One such study carried out in the Memphis area by the National Cancer Institute with the co-operation of the University of Tennessee Medical School and other local medical and health groups clearly confirms the usefulness of the 26 Pruitt, J. C., Hilberg, A. W. and Kaiser, R. F.: Malignant cells in peripheral blood. New Eng. J. Med., 259: 1161-1164, 1958. 27 Papanicolaou, G. M. and Traut, H.F.: Diagnosis of uterine cancer by the vaginal smear. New York: The Commonwealth Fund. 1943.

ADVANCES l~ C \NCKH KESK\HCH

TABLJc 4.

Type of n1.oliqnancy

can he dekck
Lesion

Carcino1na i,Jlenoc:1.rcinoroa

45

!io

:n

2l

JO

SttllHlUOllS

cell

l

8:1.rcnu1a.

Lymphoma 01.her:

2

2

0

0

0 0

0 l

]\falignant mesotrie ·

liornn . i\.:stroc_ytonm. :VIa1ignanl thy

l

rnorn_a.

()

!Vlelanum:1.

2

as an aid to

0 0

of early utninc

~~ surnmarizrs the findings obtained in t,he first examination of 108,000 womc11 "\.bout 800 wen: detected and subscHalf of these carc:mon1a which has a high cure r:itr Fully 90 per cent of these were totally The other 400 cases were invasive cancers in different stages, .30 per f'ent of which wcTe also u11suspectecL year later 33,000 of these 108,000 ,vomcn reccivi:,d a second test In this group another 83 cases of mnccr detected, of whicl1 72 were 11 invasive. in krms of rate per there wa~ a cfocrease for eancer, from :3. G dctc,,,ted on the first exami1u1tion to 2.2 on the second examination. For innisive cancer, howdrop, from 3.4 on the first ever, there was a examination to 0.3 on the second. ln other words, the invasive cancer rnte on the second screenwas only one-tenth as high as m1 the firnt

Progress has bc,cn electronic instrunwnt that the examination of the cytologic test."" The a scanning microscope', cornputer, and (fig. Glass slirles ll"ith of fluid arc placed in the \Vli ic·b prn duces information un the numllr·1· of eclls pre:sr·n (in the speeimi:,n and the size of their nu,:Iei. ()n the basis of this information, the can be classified as ucgatin°, or as furth,-.-.1 positi n, ancl then•fon· retain<"cl examination. In a stud>· of 1,0\Jii slidt·s ,-,xaminecl, 1,075 wen· known to be negative anrl 20 were known positive or suspicious. The mtc results for all tbe or sliclcs ancl 40 per cent of the negati1·c' slides mearrn that a significant. proportion of would not was ahuut twice as :1ccur:1 tF: in c,x::i.rnining slick~ from premc,noprtusa.l ns frnn, pnstrncnopausal women. ThiR diffen·nc:<· rxplainecl the fact that nonmaligtmnt cell:c with large: nueki ofteu aprwar in clusters iu the vaginal fluid of WOllWll. The succrssful rc-,mlts obtained in the stml.1 attributc~d largely to an impron·d method r,f preparing the cells in a monola~·er on the: slide~ Scientists at the National Caucr'r fnstitute· and in other .lahorntories are studying the: cation of the cytologic teclmique to tht,, der,cc:ticm of cancer of other site's, such a~ the bowel, urinary bladder, prostatt> stomach. The results of a, :1-.vear this technique mis applied to 1,561 suspcctc-cl cancer uf the gastrointestinal tnv:L wrrc reported rrcentl\ by n gnmp 11ho~c wurl< was supportrd funds from the Xational ( r:,,r lnstitute. 31 The 29 Dunn, J. E. Walton, l\l. l'rcliminary tinding.s of the County. Tenn., uterine c:a.nc:er field

An additional of the data obtained in t.he 1\Jemphis showed that invasive uterine cervic:al ca.nc-er may be asymptomatic for two to three years after onset. However, it

intcrprc:ta.tion. Presented :it A.m. Assoc. meeting, Clevelnnrl, Ohio, Nov. l:'l, l\}57

Ericksm1, C. aud asweia.Ces Popula .. trnn screc-mrng 1.1terine cancer vaginal cyt.cilog;y · prelimirrnry summary of on firsL of 108,000 women and second testing 33,000 women . .J A. :\J , 162: 167-173, Hlfio.

W L. Role of

'" Prni 1.t, ,J. C. :wd associates: H.es1.d Ls of first ,:linic:al trial of the Pr1.,sentwl

H.F. nosis of cancer of the dig:esLivP

169: 789-791, 1959.

524

JOHN R. HELLER

CYTOLOGIC TEST FOR UTERINE Results in Memphis First screening¥

lntroepithelial carcinoma of cervix

393 (3.6) 3/

CANCER

Second:,/

72 (u}3/

Invasive uterine cancer

373 (3.4) o'

i FIG.

if

II (0.3) o'

First screening - 108,000 women

~ Second screening - 33,000 women ~ Cose finding rote per 1,000 women

3. Cytologic test for uterine cancer. Results in Memphis

FIG. 4. Cytoanalyzer. This is electronic instrument under development to speed examination of specimens obtained in cytologic test for uterine cancer.

detected 95 per cent of the suspected cancers of the esophagus, stomach, and colon, and 60 per cent of the cancers of the pancreatic and biliary systems. BLADDER CANCER

The urinary organs rank fifth-after the digestive system, skin, genital organs, and respiratory system-among the principal sites of cancer for both males and female patients. The incidence of bladder cancer is more than twice as great for males as for females, but no established proof is available to account for this difference. Certain forms of cancer of the bladder are known to

have been unusually frequent in the past among persons employed in the manufacture of dyes, but the known occupational hazards probably arc responsible for only a small part of the excess of bladder cancer among males. 32 Among the studies on the etiology of cancer published in recent months is an interesting epidemiological survey on bladder cancer in Egypt and the Gold Coast in Africa. 33 The 32 Dorn, H.F. and Cutler, S. J.: Morbidity from cancer in the United States. Pub. Health Monograph, 56: 21-29, 1958. 33 Mustacchi, P. and Shimkin, M. B.: Cancer of the bladder and infestation with Schistosoma hematobiwn. J. Nat. Cancer Inst., 20: 825-842, 1958.

ADVAXCES Di C.\NCER RESEARCH

evidence obtained in tfos confirmed the hypothesis formulated many years ago that jnfcstation with Schistnsoma hernatobium is associated with cancer of the urinary bladder, While it is premature to decide that the relationship between schistosorniasis and bladder cancer is directly causal, additional studies should be made to darify this association . The theory that cytology is useful in the early detection oI eanccr of the hbcldcr is supported by results of a recent study of the urinary sediments of almost 3,000 patients over a nine-y('.ar pcriod. 34 AH the cases reported in the study wen: being treated for ailments of the genitourinary system at several Nc:w York hospitals. Cytologic examination of urinary sediments yielded correct diagnosis, positive or negative, in 60 per cent of all the cases . .!\Jost accurate results were obtained among the patients with bladder disease. A relatively low degrPe of accuracy of the: cytologic tc:st among patients ,vith kidney disorders was explained by the fact that kiclm\)' tumors do not shed cc:lls directly into urinary passages until late in the course of the disease. ,\ similarly low degree of accuracy among p3tients with prostate disorders suggested that mine: is probably not the best sample for cytologic examination and that more satisfactory results might be obtained through the use of prostatir fluid. The problc:m of the managcmc:nt of patients whos('. normal urinary flow has been disrupted a~ B, reslllt of disease or operative procedure or both has !wen studied by Jude: and Pic:per who have: reported the dc:vc:lopment of a surgical technique making use of ileum as a substitute bladdeL 35 In a number of female, mongrel dogs subjected to a proeedure in which a bladder was constructed from a (i to 12 cm. segment of terminal ileum, urinary flow was diverted through the isolated bladder and the nonfunctioning, autogenous bladd(,r was left intact. Studies of urine and blood r,bemistry carried out serially after the operation showed no romplications directly related to the operative procc:dure. These suc-cessful results have saggested clinical application of the technique in patients sl!bjected to pelvic exentc:ration. Recent experience in the treatment of ad" Foot, N. C. and associates. Exfoliative cytology of urinary sediments. A review of 2,829 cases. Cancer H: 127-187, 1958. 35 Jude. J. R. and Pieper, W. J .. Experimental temporary urinary diversion to an isolated ilea! bladder. Surgical Forum, 8: 642-645, 1957.

,'ancpd carcinoma drugs is reported by two groups of In one study, thio-TEP.-\ (tridhylenc, U1io phosphoramicle) was injected clirc,:tly into tumor of 12 patients and intran,nously in ont patient with metastases tn lymph nodes a.n, l the lungs. 36 At the time the report was three of the patients recei\"ing the iutratumnr injection showed objc:ctin, evidence of regression and one of these had had no rer-u1·rence for 2½ years. The patient with and lymph-node: mi'tastases had bC'cn free of gro,,c. evidence of disease for six months, In the second study, .5-fluorourncil ,vas according to the: treatment schedule: by Curreri. Tbc patients to \Yhom the drug: given included some: with multiple recurr1,i,c, ,s of cancer after repeated resections and other:, ,vith nonn'.sectable Jesions. 37 :\Iarked improvement ,vas demonstrated actual tmrim measurement or cystograms and remarlrnbin regression of symptoms, such as liematuria, observed. 0

EXTENT OF' CA::-lC1';H.

Cancer is the sc>cond leading 1:ause of death in the United States--second 011ly to th1, r:ardin. vascular diseases. Figures 5 and (i sbo11· some of the the pattern of cancer mortality in the United States since the early 1900's. '\Yith tht. cor,quest of tuberculosis and pncmnonia m; a, death and the increasing age of the cancer has steadily climbed to the occupies today. An estimated 450,000 new cases are every year. Deaths total about 2.'i0,000 a ye,,,r, and there are some 700,000 cases under treatment at any given time. If these trends tontinuc at the same rate, some 40,000,000 persons t1ow living ,vill develop cancer during their .lifetime' and 26,000,000 will die of it, The prevalence of cancer of varioub sites changed substantially o-ver the years. The rise observed in lung cancer in recent yearn ha, spurred intensive study of the etiology of form of cancer. Epidemiological and 36 Reynolds, L. R. and associates: with triethylene thiophospboramicle in carcinoma of the urinan bladder Proc. Am. Assoc. Cancer Res., 3: 56, 37 Wilson W. L. · The use of 5-fluorouracil for carcinomas' of the bladder. Fed. l'roc. Am. Soc. Exp. Biol., 18 1): 460,

526

JOHN R. HELLER

CANCER ASSUMES

INCREASING IMPORTANCE

AS A CAUSE OF

20

16

,mRAL DIABETES ARTERIOSCLEROSIS

Fm. 5. Cancer assumes increasing importance as cause of death

INCREASING POPULATION

+ ADVANCING

AGE=

MORE CANCER DEATHS

-

POPULATION UNDER 65 POPULATION 65 AND OVER

ANNUAL CANCER DEATHS

200

175

150

125

100

75

50

POPULATION. MILLIONS

25

00 100

300

CANCER DEATHS THOUSANDS

F'rn. 6. Increasing population plus advancing age equals more cancer deaths

studies implicate heavy cigarette smoking and the pollution of air by carcinogenic substances as factors operative in the increased incidence of lung cancer. 38- 40 The trend in leukemia as shown by analysis of recorded mortality is still upward, but the rate of increase in the past ten years has 38 Joint Report of Study Group on Smoking and Health, F. M. Strong, chairman: Smoking and health. Science, 125: 1129-1133, 1957. 39 Gelhorn, A.: The cocarcinogenic activity of cigarette tobacco tar. Cancer Res., 18: 510-517, 1958. 40 Della Porta, G., Kolb, L. and Shubik, P.: Induction of tracheobronchial carcinomas in the Syrian Golden hamster. C11ncer Res., 18: 592-596, 1958.

not been as great as in previous years. 41 A steady decline has been observed in incidence of stomach cancer in the United States during the past several decades. 42 An explanation for this decrease has not yet been found. However, suggested avenues for further study to clarify the nature of this trend include the role of endogenous factors and the influence of diet. 41 Gilliam, A. G. and Walter, W. A.: Trends of mortality from leukemia in the United States, 1921-1955. Pub. Health Rep., 73: 773-784, 1958. 42 Haenszel, W.: Variation in incidence of and mortality from stomach cancer, with particular reference to the United States. J. Nat. Cancer Inst., 21: 213-262, 1958.

.\DVAXCJ
Although tlw cpidemiologi1:al data show an ovcr--all increase in cancer since tlrn early 1900's, the mortality rate did not inerease as much as the preYalence and inc:idcnr·c rates. In IO metro-politan a.rca:s representing different geographical regions uf the United the rates in 1947 as cornpan:d with HJ37 ,vere as follo\\'s: preva1Pnce, 26 per cent higher; irn:idf'nce, 30 per cent higher; and mortality, HJ pr,r cr,nt higher. Thesr results show that encouraging progrrss has been rnade in saving lives from canc:er.41 At the turn of tlw century. a c:1UJC('l' patic•nt had little hope of snrviving. 19:38, one in four was ,;m-viving 5 years after his disease was diagnosed and today, orw in three is being savr~d . .-\ large co-operative study of medical records in the State of Connectiuit for a 17-ycar period by the 8tate Health and the Xational Cancer Institute has produced data that ma? he regarded as rdlcding a national pattern."4 In the 1935 to 1951, the 5-year survival rate increased lron1 IO to 25 per rc,nt for males arnl from 29 to 38 pc-:r cent for fomaks. 1'lw average survival rate for all cancer patients increased from 24 to :32 iwr cent. The greatest imprownient took plac:e in cancer intestine, rectum, of six important sites the and endoerirw glands in both men and \\'Omen, tlw cc1Tix ancl corpuR of the ut,•rus in wonwn, aml tlw prostate in rncn. Some impro\·crnent mis noted for cancer of the breast, kidney, and a fow other sitPs. The results were as nn i11dication of better trca.tnwnt of all incn'asingly greater proportion of canc·er

to the patkn1 One of tlw eknwnt, of rnnccr research has been the widc:ning scopr: of an increasing rrnmhrr of s,:ientists working on prog;rn1rrn that have become nationwide and m-cn worlclwicle 111 scale. Th<' at the National Cancer 1n~titute is that any scicntifical.1,1· sound wlwren"r it and a11\· g;ood ~cientist should be wppcn-ted with funds. "'1 Dorn, H.F. and C11ilc1, S . .J.: J\Iorbidit\· frnrn c,rnccr iu the. l.;nitecl States. Pub. llen11 b ·J\Iouo56: l:i5, Hl:'iS. 11. H. :111d a,.social,(,R'. Cancer in

l!:i:35-1961. C:onncetic:ut Stati,

De

Hen.Ith. HaTtford, 1D.5ii. F,ection VI. I5-GJ.

The national cancer cl1rmotherapy progr«rn is one ilhrntra,tion of the practical of this philosophy. In this program, the of a nc:twork nf hundrrcls of independent UJU· vrrsity and hospital investigators, resr'ar\'h laboratories, and industrial firms iR funds from the Institute and teclmical sr!rvic<,s of the Cancer N' ational Service Center Another illustration of the widening; scope of cancer research is found in the research grnnt~ program of the Ferlcml Government and th,, voluntary cancer organizatioH8, of which tk; A.mcricall Carn'.r,r is thP 'CJ1,, ::'-Jational Cancer Institute supports "omc I .500 research g;rants in all asprc:ts of the problem--thc c:rrnses and rmtu;-e. of r:anci-'i° diagnosis, trra.tment, and characteristic:-c n( tumor growth. Increased i,, hc,ing to virus and as a r,onsequence, th1° Imtitutc is expanding the grant,, program JP this area. In recognition of the 11cecl fnr ,1 unified attack on the .Federal Covcinmcnt is moviug iuto greater international rnrdical research activiticc program~ of the National fostitutc's oi' !-!eaJtl1. of wliich the Ca.ncer Irmtitutc is a co11;;tituenL, A grant of :noo,ooo was a warde, l the Xational Inc;titutcs of Health to Uw "\Yurld Ifralth Organization to mcdicu l rcsea,Ti, neecb ancl n:sourccs around the world rrnd stimulate~ planning for international m1'clicc1J re~e:u-ch. In addition, Lister Hill and Hub1,rt H. a bill to appropriate $50 million a .,-c:1r :i :\ational fnstitutc for Intnuational l\fedic,d Research, which would be p:i.rt of t.h1• Xatimwl Institute,~ of Hca,ltb. A similar bill ,vas introclm·l·d in the House of ,John E. Fognrty. Another element in the pattern c,f financ:ial for and clinical n:~carcl1 prog;1T1111, about $90 million lwR hecn im·c-:okd

this v,,:u b)- the i-nitcd 8tates C:uvcTrm1c:nt I~11· the cancer rcsPan.·h rt.nd relat<'d :1ctivitic's uf !he National Cancrr mi8sion, and

including the Anwrica.n Cancer Runyon .\Jrmorial Fund, Tobacco

528

JOHN R. HELLER

Research Committee, and Sloan-Kettering Institute for Cancer Research. Co-operative effort is an important element in the current pattern of cancer research. It owes its presence to the nature of cancer, which after more than half a century of investigation still remains an enigma. Again and again scientists have been frustrated in their efforts to solve the basic problems of cancer, as, for example, "what is early cancer?" The biologists, biochemists, geneticists, radiologists, epidemiologists, and, more recently, the virologists, immunologists, and serologists, have joined in the attack on cancer and have contributed tremendously to basic knowledge of cells, growth, and metabolism. Scientists are making deliberate attempts to become skilled in overlapping areas of research; for example, virologists trained in biochemistry and genetics, cytochemists, and radiobiologists are turning their efforts to cancer research. Perhaps as this trend continues a synthesis will result in which cancer research will no longer be considered the simultaneom, activity of many interdependent sciences, but a scientific discipline in its own right, and the oncologist will make use of all the basic information and powerful techniques of the contributing sciences. CONCLUSION

Sober analysis of the findings in important areas of cancer research, such as virology, chemotherapy, and cytology, has led us to the conclusion that we have reached a turning point in our work. The time has now come to enter a most difficult stage of the investigation of cancerconcentrated effort on human cancer. A review of major highlights of progress in these areas shows that the findings in virology have pointed up the importance of viruses as

causative agents in animal tumors. lt remains now to find out whether viruses cause human cancer; and if so, whether means can be developed to protect people from cancer, as is now possible in poliomyelitis, for example. Achievements in chemotherapy have generally been in laboratory development of new drugs, a few "cures" in animals, and some comparatively long remissions in patients. We must now find really effective drugs that will attack cancer tissue wherever it may be in the body and produce cures. Advances in cytology have already forged ahead in the clinic, with the result that control of at least one type of cancer-cancer of the uterus-appears to be a possibility. Our efforts must be directed toward detecting other types of cancer in the earliest stages by cytologic or other techniques. Increased effort will be made in other research areas also to identify cancer-causing or cancerpotentiating agents in the environment in which we live and work, to develop new techniques and procedures, such as in tissue culture and biochemical approaches, and to elucidate some of the mechanisms of normal and cancerous growth. Cancer research is organized and supported in a manner that was considered only remotely possible by the most visionary investigators a few years ago. The available funds have been increased tremendously, many scientific skills enlisted, techniques and instruments refined, and basic knowledge of cells and growth expanded, with the result that a concerted effort is now possible. We are aware of the magnitude of the cancer problem. At the same time, we know what our resources are and what our progress has been in the past. We believe that we shall achieve our ultimate goal-the conquest of cancer.