RECENT WORK ON THE CANCER PROBLEM CRARLES F. G B S C ~ C K GARVAN ~ R , CANCERR B S E ~ CLABORATORY, A SWGICAL PATALABORATORY OP TE3 JOHNS HOPKINS HOSPI'CAL AND UNIVERSITY,BALTIMORE, MARYLAND
OLOGY
Introduction by Joseph Colt Bloodgood* My chief reason for accepting the invitation of the editor to write an introduction to this brief, but splendid, picture of cancer research work in Europe, is to make a definite statement in regard to the organization of research work which has for its object the control of cancer in one way or another. Doctor Geschickter pictures things as they are in Europe. The conditions are about the same in this country. In both, the laboratories are isolated and, whether connected with universities or not, their relationship is not close. In both Europe and the Americas, the number of cancer research laboratories and distinct cancer clinics is too small and the number of cancer research students inadequate. The majority of the students are underpaid. Not only is the army attempting the control of cancer ridiculously small, but it is scattered, there is no real organization in each unit, nor is there any attempt at an organization of the units as a whole. The proof of this statement will be found in the report of the Lake Mohonk Cancer Convention in 1926, and the second, larger, gathering in London in 1928. The literature of the actual work in cancer research will be found in the Cancer Reen'eu published in London and in the Idex Analyticus Cancerologiae, in Paris. In spite of the educational efforts which began in Europe in 1804 and have perhaps most energetically been pursued in the United States by theAmerican Society for the Coutrol of Cancer since 1913, the enlightenment of the people through the press and other means of communication has been successful only in a few localities. The registered areas, certainly in the United States and apparently throughout the world, published mortality statistics showing that cancer as a cause of death is on the increase and has gradually risen from the twentieth place nine years ago to second place in 1929. My own studies since 1890 show that the education of the people, which brings them to the medical profession immediately after the first warning for diagnosis and treatment, increases the five-year cures from ten to fifty per cent. To have accomplished this, the enlightened individual must receive the very best surgery or the most expert radiation. Many of my own colleagues and friends in this country expressed the opinion that fifty per cent is too high a figure, but are ready to admit thirty per cent. Grant that education has accomplished an increase of twenty per cent, it is enough to justify further continuation of the efforts in every locality. The greatest criticism of cancer students-whether in the clinic or in the experimental laboratory--is that they do not enter as enthusiastically and * Director of the Garvan Cancer Research Laboratory. Clinical Professor of Surgery, The Johns Hopkins University. 1000
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intimately into the campaign of education, nor do the hospitals throughout the world, nor do the departments of health, nor as yet do the people or their representatives request the medical profession to pursue the educational control of cancer as far as possible. The department of pathology, among the sciences of medicine, has not kept pace with the demands for the diagnosis of the changing microscopic pictures as cancer comes under observation at an earlier and earlier stage of its malignancy, or in the stage that precedes malignancy, when practically, for therapeutic purposes, it is a Curable disease. Just as the majority of the medical profession has failed to realize or appreciate the value of dving the people correct information about cancer, so have the surgeons and pathologists failed to observe the changing clinical, gross, and microscopic pictures of cancer as i t comes to them when the people are enlightened and properly informed. Recent careful studies of the facts obtained in the histories of individuals who come under observation of experienced cancer students with recurrent and hopeless cancer-who have been enlightened individuals and who have sought the advice of the medical profession in the earlier stages and who have received incomplete surgery instead of the established complete surgery, or insufficient or improper radiation and not of a character now well established throughout the world-show that the number of these cases improperly treated in the earlier and more curable stages of cancer is so large as to justify bringing ;his evidence before the medical profession, so that changes can be made in d i r hospital standardization to such an extent that adequate and properly equipped cancer clinics will be established wherever necessary to meet the demands of all the people. The chief criticism in regard to research from the beginning, and especially now, is the lack of organization and the lack of cooperation between all the sciences. At the present time, in spite of all the work accomplished in all the cancer research laboratories throughout the world, there is no evidence that any of the leads briefly summarized as chronic irritation, transpldntation of animal tumors, further studies of the Rous-Murphy filtrate, cultivation of normal and cancer cells, all types of investigation of cell function and metabolism will lead to a cure. The hope of the discovery of the cause, prevention, and cure of cancer belongs to no one science. It is possible a new science may have to be discovered. The practical conclusion is, there should a t once be more cooperation and an attempt at better organization between all the sciences and investigating activities of the medical schools and universities throughout the world. For some years, in Baltimore, we have had what is called the scientific advisory board of the Maryland Cancer Committee. At its annual
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gatherings practically every medical science is represented. I t has already discussed and settled a number of important problems. The most important result, however, was a meeting this year between the cancer research studepts and the department of chemistry of Hopkins, with the result that the chemical group is aiding us in the search for a vital stain with the hope that i t will prove a differential stain for the cancer cell. The discovery of a differential stain for the cancer cell will solve one of the most difficult problems in hospital organization today. The differential diagnosis, a t the exploratory incision and with the immediate frozen section, between malignant and non-malignant cells is practically impossible in the majority of hospitals in the world today, and this is not recognized as it should he, because in the majority of the hospitals today their patients enter in the later and easily diagnosed stages of cancer. Should every individual in this country go to the nearest hospital the moment he or she is warned, then and only then would the medical profession in those clinics appreciate the difficulties in the diagnosis. The same is true of lesions of bone in the X:ray film. When Mr. Francis P. Garvan, through Mr. W. F. Keohan, generously offered to enlarge the Surgical Pathological Laboratory and to provide for research for a differential stain for cancer, I hesitated to accept until I was also promised aid in investigating to the fullest extent the records in the Surgical Pathological Laboratory and to increase the teaching force, so that we could take care of'more volunteer students. We are already reaping the benefits of this finantial aid. I t is only fair to a number of my generous patients to record here that their annual gifts aggregate a sum equal to that given by Mr. Gawan and the Chemical Foundation through Mr. William W. Buffum, the manager of that Foundation. Unless the cure for cancer is found accidentally, it will probably prove to be the most difficult piece of medical research ever undertaken, and I trust that all research students in all departments of cancer study will aid in thinking out methods of investigation and research. I take the liberty to record here briefly my own point of view based on more than thirty years of study, familiarity with the literature, correspondence and personal contact with many men and women interested in the whole wide field of cancer. The fundamental basis of cancer study was clinical until the discovery of the microscope, and during that period there were no cures, little or no improvement in treatment. It is remarkable what Velpeau did in his pathological and clinical studies without the aid of the microscope. In fact he made classifications that have stood the test of microscopic reinvestigation. After the development of cellular pathology started by Virchow and dependent upon differential staining of microscopic speci-
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mens, the classification of benign and malignant neoplastic diseases made rapid advances, and has practically reached its limits today. Nevertheless there are still differences of opinion about the classification of such lesions as the giant-cell tumor, multiple myeloma, Hodgkin's disease, and so forth. But these studies did not advance rapidly the treatment of cancer. Without doubt, the operative treatment of cancer did not rest upon a pathological basis, but was made possible by anesthesia which allowed the long, painstaking dissections, and Lister's antiseptic surgery which made it safe to pursue these long dissections without the danger of blood poisoning from an infection of the wound. The surgery of cancer really began in 1x84 with Billroth's resection of the stomach for cancer. This was followed by Halsted's conception of the radical operation for cancer of the breast in IS89 or earlier, then by Kraske's method of complete iemoval of the lower end of the rectum with the coccyx and a piece of the sacrum, and then by Werthheim's most radical removal of the uterus with its lymphatics for cancer of the cervix. These surgeons who conceived these radical operations for cancer were trained surgical pathologists and knew, from actual pathological study, the extent of involvement of the malignant disease from the primary focus. I know of no exception to the rule that a surgeon who established a pioneer operation for cancer was a gross and microscopic pathologist. This statement is true today. To maintain the results from the operative treatment of cancer, the operator today must not only have the same skill as shown by Billroth, Halsted, Kraske, Wrthheim and others, but the same knowledge of gross pathology. This type of surgery in that first decade to 1900 accomplished ten per cent of cures even in late cancer. Today the operator has another burden and responsibility. The older surgeons did not need their pathology so much to know how to diagnose the cancer they were attempting to cure, but to conceive how much tissue in addition to the local growth must be removed by a most painstaking bloodless operation, in order to give the patient ten per cent chances of a cure. The operator today, if he wishes to increase the chances of a cure from fifty to more per cent and never to make the mistake of an incomplete operation for cancer, or too extensive and mutilating an operation for a local lesion that is not cancer, must either himself be a trained surgical pathologist, or have one constantly with him in the operating room, just as he has an anesthetist or assistants in the technic of the operation. Microscopic pathology, therefore, is still the basis of successful operative treatment of cancer today. For this reason, in the Surgical Pathological Laboratory of The Johns Hopkins University, with our added income, we have been able to increase our teaching force so that we are actually teaching seventy-five to one hundred s t u d e n t s a l l volunteers-where before we could teach only twenty-five. The groups are limited to twenty-
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five students. The Garvan Research Laboratory for the differential stain of the cancer cell adjoins the teaching laboratory. Research and teaching proceed together, and from the students who take the course in microscopic surgical pathology throughout the four years in the medical school, we hope to get our research students and future operating surgeons. Although we have already developed, in many clinics throughout the world, the successful cultivation of the normal and cancer cells of animals, we have as yet not succeeded in doing so with the human cells. With the help of the Chemical Foundation, this laboratory has been established and is working. We hope to use the growing human cancer cell in our studies of the differential stains and many other as yet unsolved problems which may, lead to the discovery of the cause, prevention, and cure of theuncontrolled cell activity called cancer. For various experiments a well-established and uniform strain of animals, especially rats, are necessary. We are planning to create such a large establishment of experimental animals that we may meet the real demands for a larger cancer study. It is my hope that as we become mdre and more familiar with the clinical, pathological, therapeutic, and research studies on cancer throughout the world, we will be able to pick out the best in the various clinics and laboratories and bring this type of investigation together in one great clinic, and demonstrate to other clmics the kitid of an organization which promises most for the best control of cancer today, and most for the discovery of its cause, prevention, and cure. I also venture the opinion that the most important thing that has happened to make this possible is the launching of a new journal on cancer by Mr. William W. Butfum, Manager of the Chemical Foundation, which has the approvalof Mr. Garvan, the President of the Foundation, and the Trustees. Charles F. Geschickter's Summary of Cancer Problem The increasing popular interest in the cancer problem, stimulated largely by current newspaper reports, bas resulted in a great diversity of opinion concerning the present status of work on the cause and cure of cancer. To the lay mind cancer is a single disease entity, and the heavy mortality for which it is responsible bespeaks uniform incurability. As a matter of fact neither of these assumptions is correct. There are as many different types of cancer as there are tissues in the body, the glandular tissues, such as the liver and the breast, giving rise to a group of cancers known as carcinoma, and the supporting tissues of the body, such as bone and various types of so-called connective tissues, giving rise to forms of cancer known as sarcoma. Neither the various forms of carcinoma nor sarcoma
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are uniformly fatal, and cures may be established by complete removal early in the disease before the cancer cells in the tissue involved migrate elsewhere to other organs to start multiple new colonies known as metastases. The problem in the treatment of cancer at present therefore is not merely to cure those cases which come under observation early with the local disease, but to treat successfully those cases which have dissemination or metastases or are seen late when the disease is widespread. The quest for a cancer cure is thus complicated by the variability of the disease and its tendency to secondarily involve many m e r e n t organs in the body. Work on the problem of the cause of cancer is even more involved since it undertakes the explanation not only of how the usually fatal growths or malignant tumors of carcinoma and sarcoma arise; but also must account for the origin of the so-called benign tumors which resemble the malignant tumors in their cellular composition and in that they are abnormal growths of tissue which serve no physiologic purpose although they closely duplicate the structure of the organ in which they arise. Unlike the malignant tumors, however, the benign tumors are characterized by slow or arrested growth, and have no tendency to migrate to distant organs to produce metastases which result fatally. The benign tumors may persist without operative interference and although producing local disturbances may never kill while the malignant tumors are invariably fatal when left to pursue their natural co*urse. I t is not always easy to determine the preseece of a tumor arising in an internal organ, and even after the presence of the tumor is established, operation to remove a piece for examination under the microscope is often necessary to determine whether the growth is benign or malignant, and even with the aid of the microscope the distinction is not always easily made. Means for accurate diagnosis between benign and malignant tumors is still an important problem for cancer research workers. The various lines of investigation in the cause, diagnosis, and cure of cancer have become so diversified, that a tour of investigation of the larger cancer laboratories in Europe as well as a fmt-hand acquaintance with work in this country is perhaps the only reliable means of estimating the present state of progress in this broad field of medical endeavor. In the following pages an attempt has been made to summarize the results of such an investigation conducted during a four months' stay in Europe.
I. Work on the Cause of Cancer Progress in the realm of cancer research appears to he dependent upon a gradual accumulation of facts rather than upon revolutionary and outstanding discoveries. The accumulation of this information necessary to the support or revision of cnrrent conceptions in regard to the cause
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of cancer requires new methods of research and experimentation, and it is in the gradual extension of such available methods that the greatest progress toward the goal of solving the cause of cancer is being made. Thus in the past decades methods of cancer investigation have passed from the pathologic technics of dead and fixed specimens to animal experimentation, and in more recent years from animal experimentation to a direct study of human material in its living state in the form of cell suspensions, and possibly to tissue culture. It cannot be said therefore that work on the cause of cancer is a t a standstill merely because no new principle of tumor origin has been demonstrated. Thus, a survey of the cancer laboratories in Europe reveals uncertainty and speculation in regard to the cause of malignancy, and yet there is evidence everywhere of an attack upon the problem along more fruitful and scientific lines. The experimental methods used and not the theories of cancer met with will therefore receive chief emphasis in this report. Two main lines of inquiry which have occupied the center of attention of workers on the cause of cancer for some years are the result of experimental work on laboratory animals (including mice, rats, and chickens). One of these lines of inquiry is directed toward the analysis of irritating chemical agents such as the coal-tar derivatives and is based on the experimental production of carcinoma in rats and mice by skin irritation with these injurious agents. The other field of inquiry is directed toward the analysis of tumor filtrates in the'search for evidence of a sub-microscopic infecting organism or filterable virm, or for some growth ferment or biologic catalyst influencing cell reproduction. It is based upon the laboratory procedure of transferring the sarcoma in a chicken from fowl to fowl by means of a cell-free filtrate prepared from the tumor. The older field of experimentation is with tar cancer. Carcinogenic Agents-Chemical
Imtants Producing Cancer
Dr. Ernest I,. Kennaway, chemical biologist a t the Cancer Hospital Research Institute in London, is continuing his experiments with cancer production in mice by means of coal-tar derivatives (Figure 1). Attempts have been made to produce effective carcinogenic agents in the form of synthetic compounds in the hope of disclosing some common chemical basis to all of the cancer-producing irritants. So far, in the cancer hospital laboratories they have never produced cancer in an animal by any pure chemical substance, although complex substances such as coal tar will produce true, malignant tumors on repeated application. One branch of their work has been stimulated by the occurrence of bladder cancer in dye workers, but their attempts in the past five years to produce bladder cancer in mice and rats by dye injections have not been successful. Workers in other laboratories, such as Dr. Carminati working under
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FIGURE
1.-THE
RECENT WORK ON CANCER
CANCEKHOSPITALKESGARCH
INSTITITTE ON
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I:CLIIAM KOAD,
LONDON, ENGLAND. UNDER THE DIRECTION OF DR. ARCHIBALD I,EITCH Dr. Ernest L. Kennaway's experiments on cancer production in mice by means of coal-tar derivatives arc being conducted at this Institute.
Professor Pedro Rondoni of Experimental Biology in the Victor Emanuel National Institute in Milan, are conducting similar experiments with the coal-tar derivatives. However, in most of the European cancer laboratories the attitude toward this field of investigation is one of disappointment. This attitude does not detract from the value ol tumor production
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by' carcinogenic agents as an experimental method, for it is proving a valuable tool in the hands of many investigators for the study of the earliest stages of cancer formation which may be thus produced. From the standpoint of cancer causation, the results obtained from this method of tumor study lend weight to the time-worn theory of Virchow, that chronic irritation in tissues is a factor in cancer production, and would seem to indicate that the specific feature resides in some tissue change induced, rather than in the physical or chemical property of the injurious agent. No light, however, has been thrown upon the mechanism whereby the cancer change is instituted. One significant limitation of this method is that it is practically confined to external tissues such as the skin and has not been successfully applied to internal organs such as the stomach. Tumor Filtrates By far the most prevalent mode of study of the origin of cancer is that conducted upon tumor filtrates with the Rous chicken sarcoma.' The malignant, death-dealing nature of this tumor, as well as its inoculation from one fowl to another by means of a cell-free filtrate, is generally accepted by all cancer workers as proved. The search for the potent factor in the filtrate, however, continues. The hypothesis entertained widely some five years ago that the specific agent in this filtrate was some form of submicroscopic organism or filterible virus bas been abandoned in practically all of the large centers of canner investigation. The renewed interest in this subject has come from the experiments of Murphy a t the Rockefeller Institute in New York, and of Luther Heidenhain in Worms, Germany. Since Murphy startled the London Cancer Conference in 1928 by announcing that he had demonstrated by experiments on the Rous sarcoma that cancer is caused by a ferment or biologic catalyst capable of influencing cell growth many workers have sought to confirm his results. Among those engaged along these lines are Charles Sternberg in Vienna, Max Borst in Munich, Archibald Leitch, and James Murray in London. Murphy based his conclusions upon the pkoduction of sarcoma in chickens by the injection of extract of normal testicles. Leitch achieved the same results by injecting the extract of normal pancreas into fowls. But neither Murphy nor Leitcb have been able to repeat their own experiments with constant results, and the work of other investigators has led to the conclusion that the effects of the extracts thus prepared were entirely nonspecific and the tumors produced either a chance occurrence or the result Rous chicken sarcomasarcoma of the chicken known by the name of Raus sarcoma, because it was first described by Rous. [See Rous. J. Exper. Medicine, 12, 696 (1910).]
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of contamination with the Rous sarcoma filtrate. A similar interpretation is being placed upon the experiments of Carrel who obtained sarcoma in fowls by injection of arsenic and indol. The work on tumor cell filtrates in cancer has been practically limited to the chicken and the production of chicken sarcoma, and for this reason skepticism is beginning to grow in regard to the conclusions drawn by experimenters in this realm in regard to human cancer. However, the work of Luther FIGURE 2.-A MI~ROPEIOTOGRAFH SHOWING THE Heidenhain has been adTYPEOP CELLSIj4 ONE OI. THE TUMORS PRODUCED vanced in support of the IN MICE BY HEIDENHAIN conception that tumor This tumor was pr&uced by a cell-free filtrate. filtrates have a wider The original filtrate was prepared from a fatal human tumor comoosed of cartilaze. and was iuiected into significance. Heidenhain a mouse wiih the production of a cancer of t h e breast. (see Figure 2) prepared A second filtrateprepared from this cancer in the mouse produced this third tumor shown in the picture, a n e x t r a c t from a which resembles in structure the original human fatal human tumor comtumor. ~ o s e dof cartilace (chon- . drosarcomaq) and produced a very different but equally fatal growth (adenocarcinomaa) by injecting it into mice. On successive transplantations, this adenocarcinoma finally showed cartilaginous deposits and Heidenhain concluded that a specific tumor-producing agent had been present in his filtrate. This work of Heidenhain has not yet been confirmed. Borst in Munich, although skeptical, believes the experiments worthy of repetition. Charles Sternberg in Vienna was favorably impressed but Blumenthal in Berlin and Murray in London are inclined to the belief that the mouse tumor of Heidenhain was a spontaneous occurs Chndrosarcomaa tumor composed of rapidly growing cartilage (or gristle) arising in bone, and hence a sarcoma. 2 Adenorarcinoma--a malignant glandular tumor with cells arranged in ring-like formation.
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rence and not the result of the filtrate prepared. It is hoped by some observers, such as Borst of Munich, that the Heidenhain experiments will bring the question of tumor filtrates to a crucial test, and determine whether or not this line of research is applicable to human carcinoma. Certainly, in view of the great vogue that the Rous tumor experiments have been enjoying, it is time that some reliable check was made to determine the value of the results obtained, from the standpoint of human malignancy. Tumor Metabolism The extension of biochemical methods to cancer investigation is largely due to Otto Warburg and his co-workers in-the Kaiser Wilhelm Institute
Abb. 2.
FIGURE 3.-THE APPARATUSUSED BY WARBURG FOR METABOLISM OB LIVINOTUMOR The general view of the apparatus "Abb. 2" shows the manometer ( B ) connected with a shaking apparatus, the parts of which are indicated by the letters SC4 R. E, and Tr. The manometer is attached to the water bath Tk and leads by a tube D to the tumor under investigation. The apparatus marked "Abb. 3" shows in greater detail the device for holding the tnmvr t o he studied. The thin piece of tumor tissue S is immersed in a physiologic solution and held on a needle N. The glass container E and G is capped by the glass tubing H a n d T, which leads t o the manometer shown in "Abb. 2."
of Biology in Berlin. Warburg by an application of the manometric methods (see Figure 3) of gas analysis of Barcroft to living tumor tissues has contributed valuable measurements on the metabolism of living tumor cells. These experiments conducted over a period of the last six years have shown that tumor cells utilize carbohydrate by two methods. One of these, combustion of sugar by means of the oxygen breathed, requires air and is termed aerobic. The other takes place without the aid of oxygen and is termed anaerobic. It consists of splitting sugar to lactic acid
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(glycolysis) in the absence of oxygen. Both methods of carbohydrate metabolism are found in all tissues, but cancer tissue, according to Warburg's findings, is nnique in the magnitude of its glycolysis, and even in the presence of oxygen this form of carbohydrate metabolism predominates with the formation of large quantities of lactic acid, which accumulate in a manner not found in other tissues. This glycolytic capacity of tumor tissue enables it to survive under anaerobic conditions, and upon this finding and the fact that tissues from the embryo also have a high rate of glycolysis, Warburg has constructed a metabolic theory of tumor origin. He postulates that embryonic cells4 are sprinkled throughout normal tissue (probably for purposes of repair) and that when the tissue is subjected to an I1n,fe5-or Ikmt i s onr of the world amhoriries oxygen want by scarring of on tlw p a t b u l u ~ y of cmcrr 311d i*i ~ u t h w
