Therapeutic Revolution: The History of Medical Oncology from Early Days to the Creation of the Subspecialty E-Book
Pierre R. Band
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2014
Cancer is a disease responsible for several million annual deaths among humans, worldwide. However, advances in healthcare - which include breakthroughs in science and medicine as well as access to medical treatment - have improved the survival rate of cancer patients over the last few decades.
Therapeutic Revolution relates the story of one of the great scientific tales of the twentieth century: how the field of medical oncology was created and its development owing to medical and scientific breakthroughs. The book unfolds the pre-clinical and clinical concepts and innovations that led to the creation of the medical subspecialty now known as medical oncology.
Therapeutic Revolution is the first book ever written on the events that led to this subspecialty of internal medicine. It relates the recollection of key events obtained from interviews of the pioneers who laid the foundations of medical oncology, as well as the author’s own experience of the pre-specialty era of medical practice.
The book is essential reading for medical oncologists and for all readers interested in the history of cancer treatment and also serves as a historical primer for medical students learning oncology.
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FOREWORD
History is written by the victors. Although the vanquished may offer explanations, excuses or speculative essays on what it would have been like had they won, such efforts rarely depict reality. Often a victory is described by someone who was remote from the battle, a historian distant in time, with no passion and scars from the conflict. Pierre Band is not that kind of historian. He was fully engaged in the extraordinary turbulence that permeated the early years of medical oncology.
Surgery for cancer had existed for many hundreds of years, although anesthesia only appeared in the 1840s. Ovariectomy was introduced for breast cancer in the 1890s and castration for prostate cancer in the 1940s. Radiotherapy for cancer began in the early 1900s. Nitrogen mustards were explored as cancer drugs in the 1940s, under cover of wartime secrecy. The excitement really began in the late 1940s, when aminopterin was shown to induce temporary remissions in children with acute leukemia. Acute leukemia of children then became the first target of opportunity for scientists and doctors who were not surgeons. Principles of cancer chemotherapy were unraveled and chemotherapy began to be used in solid tumors immediately post-surgery and then before surgery, within the setting of rigorous clinical trials.
Dr. Band unfolds this fascinating story with the familiarly of a participant, drawing upon his correspondence and interviews with most of the main characters, and imbued with the excitement of this dynamic and revolutionary tale. The story of how a new discipline in medicine came about, bringing the promise of eventual triumph over cancer is among the great tales of the twentieth century.
This book tells that story. It is a record of struggle and triumph that sets the record straight. May it inspire young minds to pursue new quests to finish the task and open new vistas for improving the human condition.
PREFACE
Many books have been written about cancer and many articles have been published on the history of chemotherapy, but none to our knowledge on the history of medical oncology, that is, the events that led to this new subspecialty of internal medicine, which was first established in the United States in 1972. As a medical oncologist, I had been thinking of writing a book on this subject and discussed the idea with Dr. Roberto Zanetti, Director of the Piedmont Cancer Registry in Torino, Italy, with whom I had spent a mini-sabbatical. He encouraged me to go ahead, despite my hesitations as I am not a historian. Before deciding to proceed, however, I first wanted to test the ground by preparing a set of slides for potential lectures. Zanetti kindly invited me, with the financial contribution of the Fondo Anglesio Moroni in Torino, to give a series of talks in Torino, Parma and Florence, Italy. All my talks were well received.
Serendipity being what it is, I had read a paper by Dr. Franco Muggia discussing the screening of cancer chemotherapeutic agents, an important topic in the early days of medical oncology. Muggia and I were members of the Eastern Cooperative Oncology Group; although we had no contact for many years I phoned his office in October 2009, to tell him of my plans. Muggia, the Chairman of the annual Chemotherapy Foundation Symposium, invited me to speak at its XXVIIth conference, to be held the following month in New York City, a talk that was subsequently published [1]. There were about 2000 people in the audience, mostly medical oncologists and oncology nurses of various ages. I then gave a similar presentation in Montreal on receiving the “Pioneers in Canadian Oncology Award” from the Canadian Medical Oncology Association. Judging from the comments received, I realized that the history of medical oncology was a subject of great interest and possibly a gap to be filled, at least from the perspective of the younger generation.
Since my talks included an overview of the history of cancer that preceded the first modern treatment of malignant diseases, I intended to gain access to the Osler Library of the History of Medicine at McGill University in Montreal. To do so conveniently, for instance to access electronic material at the McGill libraries from home, I needed a Faculty appointment at McGill University. For this, I owe sincere thanks to Dr. Phil Gold, Professor of Physiology and Oncology at McGill University, who kindly arranged for me to be granted an appointment in the Department of Medicine.
At the same time, I had the chance to interview or talk on the phone to the pioneers who laid the foundations of medical oncology. A large part of this book relates their recollection of key events.
REFERENCES
[1]Band PR. The birth of the subspecialty of medical oncology and examples of its early scientific foundations. J Clin Oncol 2010; 28:3653-8..ACKNOWLEDGEMENTS
I cannot overemphasize my gratitude to everyone I have had the chance to contact or work with. Without them this book would not have been possible. They are: Doctors Gianni Bonadonna, Robert W. Bruce, Nicholas Bruchovsky, George Canellos, Paul P. Carbone, Bayard Clarkson, Andrew Coldman, Richard Cooper, Vincent De Vita, Bernard Fisher, Emil Frei III, Emil J. Freireich, Phil Gold, James Goldie, Thomas C. Hall, Jules Harris, James F. Holland, Jimmie C. Holland, John Kelsey, Lucien Israël, Irving Johnson, Irwin Krakoff, Harvey Lerner, Larry Norton, Georges Mathé, Franco Muggia, Hyman Muss, Albert Owens Jr., Joseph Ragaz, Maurice Schneider, Janet Wolter and Roberto Zanetti, as well as Lois Trench and Scott Kennedy.
Special thanks go to the McGill librarians for their ongoing assistance, and to John Stewart and Dr. Cornelia Hentzsch of Purdue Pharma, for a grant that enabled me to meet, interview and film Doctors Frei, Freireich and Holland. I am indebted to Diana Thiriar and to Christian Band for grammatical and other editing and to Helmut Bernhard of Neuro Media Services at McGill University for his professional help with the iconographic material and also for contributing his expert touch to improve the photographs that I took.
I owe particular gratitude to my mentor Dr. James F. Holland for his editorial comments and numerous helpful suggestions, to my friend and colleague Dr. Nicholas Bruchovsky for his painstaking editing of the entire book and to Kathe Lieber for professional editing of the final text.
There is no conflict of interest for the ebook.
DEDICATION
To the pioneers of medical oncology
To the patients who made it possible
The Author Introduces Himself
Pierre R. Band*Abstract
During his internship in 1961, the author sent letters of inquiry asking which centers in the United States provided a residency program in cancer medicine and what kind of training was offered. The answers were unexpected. Not only did these simple questions appear to be difficult to answer, but one reply indicated that a cancer specialist was a non-entity! The author briefly describes the training he received from two of his mentors, Dr. Georges Mathé in France, and Dr. James F. Holland in the United States, exemplifying what existed at the time when the methodology of clinical trials was being developed and the experimental bases of chemotherapy were being conceived and tested within the setting of cooperative oncology groups.
Introduction
I was born in Paris to Hungarian parents and immigrated to Canada when I was 15, leaving behind close friends at an age when identification with a group takes on major importance. The shock must have been violent: I became a high-school dropout and worked at a restaurant in Montreal called Ben’s that was famous for its smoked meat sandwiches. After a year of preparing smoked meat and pickles I decided to go back to school, working very hard to compensate for the time lost. It took courage from the professor who interviewed me to allow me to enter medical school at the Université de Montréal, considering my unorthodox track record. During my internship in 1961, I pondered what career to pursue. I did not want to follow common paths nor specialize in diseases of a single organ, such as the heart, or a system, such as the gastrointestinal tract, but wished to remain close to internal medicine. And so I opted for cancer medicine. It was an easy decision: there was little else to choose from and it did not exist! One of the professors of pathology, who was on the Board of the National Cancer Institute of Canada, advised me to apply for a fellowship and suggested that I should consider the Institut Gustave-Roussy, the main cancer center in France.
I also sent out letters of inquiry asking two simple questions: what centers in the United States provided a residency in cancer medicine and what kind of training program they offered. The replies were unexpected. The American Medical Association informed me that “There are no longer any formal residency training programs in cancer, malignant diseases or oncology” (Fig. 1.1). If that first answer was not very encouraging, I was bewildered by the second, from the American
Figure 1.1)Letter received from the American Medical Association.
Cancer Society: “First off, there really isn’t any recommended special training for oncology because the clinical and oncologic specialty system of medical practice determines the course of treatment of the cancer patient, thus making a ‘cancer specialist’ a non-entity” (Fig. 1.2). Finally, what I thought were straightforward questions seemed difficult to answer, judging from the reply I received from the National Institutes of Health (Fig. 1.3). Despite this discouraging news, I went on to spend several years of training in cancer medicine in the departments of Dr. Georges Mathé (Fig. 1.4) at the Institut Gustave-Roussy, Villejuif, France, and Dr. James F. Holland (Fig. 1.5) at Roswell Park Memorial Institute, Buffalo, New York. I owe to
Figure 1.2)Letter received from the American Cancer Society.
these mentors the opportunity to have lived, and contributed to some of the most exciting and stimulating pioneering years of medical oncology. Those were the days when the methodology of clinical trials was being developed and the experimental bases of chemotherapy were being conceived and tested within the setting of cooperative oncology groups. The torch of knowledge is passed from one generation to the next. Holland and Mathé belonged to the first generation of pioneers in oncology. I had the good fortune of being among the second, close to the precursors, many of whom I had the chance to meet.
In turn, I would like to share with the younger generation of medical oncologists a personal overview of what paved the way for the specialty they have elected to embrace.
Figure 1.3)Letter received from the National Institutes of Health.
Mathé, who died in 2010 at the age of 88, was a hematologist and immunologist who took postgraduate training in immunology and oncology at Memorial Sloan-Kettering Cancer Center in New York City. He became recognized worldwide not only for having performed the first bone marrow transplant in non-identical twins, but for the very unusual circumstances under which the procedure was initially accomplished: the treatment of Yugoslavian physicists who had been irradiated during a nuclear reactor accident [1]. In 1961, Mathé became head of the Department of Hematology at the Institut Gustave-Roussy, where he carried out experimental and clinical research in bone marrow transplant for the treatment of acute leukemia and other malignancies. Mathé was one of the founding members and first president of the Groupe européen de chimiothérapie anticancéreuse, a clinical cooperative oncology group that became the European Organization for Research and Treatment of Cancer (EORTC) in 1965. With Dr. Maurice Schneider, one of his former staffmen, he founded the European Society for Medical Oncology in the mid-seventies.
I arrived in Mathé’s department in July 1964 after two years of residency in internal medicine in Montreal. As a resident (or intern, as they are called in France), I was responsible for about 25 inpatients, mostly children and adults with acute leukemia. I had the opportunity to learn about this disease, its dreadful complications and the familial impact of malignancies, and to participate in clinical trials of investigational chemotherapeutic agents, some of which were part of the Groupe européen de chimiothérapie anticancéreuse studies.
Figure 1.4)Dr. Georges Mathé (left) and Maksic Radojko, one of the Yugoslavian nuclear physicists who underwent the first bone marrow transplantation in January 1958. Photo taken at the inauguration of the Georges Mathé Cancer Center in Belgrade in 2007. Photo taken and kindly provided to the author by Michelle Chaker, Executive Secretary, Institut André Lwoff, Villejuif, France.
In January 1966, I joined the department of Dr. James F. Holland, Chief, Medicine A, at Roswell Park Memorial Institute, as a National Institutes of Health Post-Graduate Fellow. Holland’s contributions to cancer medicine will figure prominently in this book. Suffice it to say here that Holland was the first attending physician at the National Cancer Institute when the National Institutes of Health in Bethesda, Maryland, opened its Clinical Center, where he developed what was to become the first-ever clinical cooperative trial in childhood acute leukemia. Holland was a founding member of the Acute Leukemia Group B (ALGB), which he chaired from 1963 to 1981.
Adjacent to his small office was a slightly bigger room, essentially occupied by a table where the staff, fellows and residents used to crowd together when he wanted to share important information with them. It was there that one day I asked Holland what my project would be. He pulled from the pocket of his white coat a small plastic container filled with pills, placed it in the middle of the table, told me this was my project and left. The container had a number written on it: NSC 29630; so I went to the pharmacy department to ask whether the number was by any chance linked to other less cryptic information. After being told that the pills were called dichloromethotrexate, I informed Holland of what he already knew. He told me I should carry out a Phase II study of that compound. Since I had little knowledge of how to do that, I read up intensively on the methodology of experimental and clinical drug evaluation and whatever was known of NSC 29630. When Holland and I met again in that same room, he must have been pleased with my progress, because he told me to write a Phase II protocol for the drug in question, carry out the study in lung-cancer patients and write a paper. Before leaving, as a token of his appreciation, Holland wrote the following words on a slip of paper: introduction, method, results, discussion, conclusion. The study was done and published. This is a true account of what happened, and I regret to say that this type of training has largely been forgotten.
Figure 1.5)Dr. James F. Holland. Photo taken by the author; New York City, November 2010.
In 1968, before returning to Canada, I applied for positions in medical oncology. Once again, the replies were unexpected. The head of the Department of Medicine at a major teaching hospital where one hematologist was treating cancer patients told me that “two cancer specialists would step on each others’ toes”. The most laudatory reply came from a provincial Canadian Cancer Center stating that I was overqualified for the job. Cancer medicine must not have been considered to be a very attractive profession. This was the situation at the time in Canada, while in the United States comprehensive cancer centers and separate divisions of oncology were being set up, offering career opportunities to many young oncologists, including several of my Canadian colleagues.
At last a positive answer arrived from the University of Alberta in Edmonton, which I joined in July 1969. My first undertaking was to apply for membership in the Eastern Cooperative Oncology Group (ECOG); the University of Alberta thus became the first Canadian center affiliated with this group. I also became a member of the EORTC. While in Edmonton, I became involved in therapeutic trials in breast cancer that will be discussed in later chapters of this book. An important development at the time was the discovery of the carcinoembryonic antigen by Doctors Samuel Freedman and Phil Gold at McGill University in Montreal. It was hoped that a test of this antigen in the blood would make it possible to diagnose colon cancer at an early stage. I participated in collaborative studies investigating this antigen and heard a presentation by a cytopathologist, Dr. Geno Saccomanno (1915-1999), stating that there was a positive association between titers of the carcinoembryonic antigen and the degree of sputum cytology abnormalities. Saccomanno (Fig. 1.6) began his career on the Colorado Plateau, where a number of uranium mines were operating. By taking serial sputum cytology samples from underground miners, he had described the development of lung cancer from normal cells to mild, moderate and severe atypias, to cancer in situ and invasive cancer [2], receiving the Papanicolaou Award for his work.
Since there was a uranium mine in the north of the province of Saskatchewan, with a company plane flying daily from Edmonton to the mine, I approached Saccomanno, asking him if he would be interested in a joint study investigating the role of the carcinoembryonic antigen and sputum cytology for the early detection of lung cancer in this high risk group. He agreed, and we conducted a study [3, 4] that would have a considerable influence on my career. First, because several cases of moderate and marked atypias where found among the miners we studied, I became interested in chemoprevention and the potential cancer-preventive effect of vitamin A and its synthetic analogs, which had been the subject of a recent publication [5]. Second, contacts with uranium workers gave me a keen interest in occupational health issues.
Figure 1.6)Doctors Geno Saccomanno (left) and George Papanicolaou, the father of cytology. Photo taken in February 1962, when Dr. Saccomanno received the Papanicolaou Award, 9 days before Dr. Papanicolaou’s death. Photo kindly given to the author by Dr. Saccomanno.
This brought me to the British Columbia Cancer Agency in Vancouver in 1982 to set up a program in occupational cancer epidemiology, which became my main activity, although I continued to work as a medical oncologist, but in a more limited manner. I was surrounded by outstanding colleagues and friends among them Doctors Nicholas Bruchovsky and James Goldie (Fig. 1.7).
Bruchovsky’s demonstration that dihydrotestosterone is the active form of testosterone in the prostate radically changed notions of androgen physiology and physiopathology [6, 7]. Goldie’s mathematical model developed with the statistician Dr. Andrew Coldman, triggered worldwide interest in the preoperative chemo-therapy or neoadjuvant approach to cancer treatment [8].
Figure 1.7)From left to right: Doctors Nicholas Bruchovsky, Pierre Band and James Goldie; Vancouver, 1998. Author’s collection.
I left the Agency in 1996. The years spent there count among the most memorable of my professional life.
REFERENCES
[1]Mathé G., Jammet H., Pendic B., et al. Transfusions and grafts of homologous bone marrow in humans after accidental high dosage irradiation.Rev. Fr. Etud. Clin. Biol.19594226238[2]Saccomanno G.. Diagnostic Pulmonary Cytology.ChicagoAmerican Society of Clinical Pathologists1978[3]Band P., Feldstein M., Saccomanno G., Watson L., King G.. Potentiation of cigarette smoking and radiation: evidence from a sputum cytology survey among uranium miners and controls.Cancer19804512731277[4]Band P., Watson L., Saccomanno G., et al. Sputum cytology and carcinoembryonic (CEA) survey of uranium workers.Prevention and Detection of Cancer.Nieburgs H.E.New YorkMarcel Dekker, Inc.1978671682[5]Sporn M.B., Dunlop N.M., Newton D.L., Smith J.M.. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids).Fed. Proc.19763513321338[6]Bruchovsky N., Wilson J.D.. The conversion of testosterone to 5α-androstan-17β-ol-3-one by rat prostrate in vivo and in vitro.J. Biol. Chem.196824320122021[7]Bruchovsky N., Wilson J.D.. Discovery of the role of dihydrotestosterone in androgen action.Steroids199964753759From Dinosaurs to the Dawn of Chemotherapy: A Brief Overview
Pierre R. Band*Abstract
A brief overview is presented, from early findings of malignant tumors to the beginning of modern chemotherapy. The humoral, lymphatic and cell theories of cancer are summarized, as well as major scientific developments and discoveries in medicine and oncology, such as anatomy, physiology and pathology, inhalation anesthesia, radiation and hormonal procedures. The contributions made by key scientists and physicians are emphasized.
INTRODUCTION
Although the history of modern medical oncology dates back little over half a century, cancer diseases have long been present. Evidence for the antiquity of malignant tumors comes from fossilized bone material and mummies and from early written documents. Primary and metastatic bone tumors have been found, albeit extremely rarely, in fossilized bones of dinosaurs and other animals [1-5], and have been recognized in Ancient Egypt and in the Pre-Columbian Incas [6-8]. Autopsies, radiographies and biopsies of mummies and other bone remains have shown involvement with various cancers, most commonly nasopharyngeal and multiple myeloma, but also with other types [6-8]. The first written record of cancer comes from the Edwin Smith papyrus of Ancient Egypt, where a case of breast cancer was reported with a comment that there was no treatment [9].
THE HUMORAL THEORY OF CANCER
Cancer medicine in its conceptual aspects may be traced to Ancient Greece, where medicine was practiced by physicians instead of priests, as was generally the custom in Mesopotamia and Ancient Egypt. Reason replaced faith and superstition, and diseases became attributable to natural causes rather than to the wrath of the Gods: “Each disease has a natural cause and without a natural cause none occur” [author’s translation, reference 10]. The term “onco,” which became the root of the word oncology, referred to swellings or masses of any origin, whether malignant or not. The Greek physician Hippocrates (460 BC-375 BC) coined the term karkinos, meaning crab, for malignant tumors; the name likely comes from malignant tumors’ resemblance to the shape of a crab, with a hard round center and leg-like projections. Hippocrates described visible or readily palpable cancers including those of the skin, head and neck, breast and cervix. His descriptions of virilization in two women who died of their disease are of special interest: “Menstruation ceased and the body took on a virile appearance, this woman became hairy all over, she grew a beard, her voice acquired harshness . . . this woman died in a short time” [author’s translation, reference 11]. These cases (the second woman had the same clinical findings) may be the first-ever reported of virilizing ovarian or adrenal cancers, which at that time could not be diagnosed as such.
The cause of cancer was based on the theory of humors. This theory originated from the School of Pythagoras, which considered the number four, the sum and product of two equal numbers, to represent nature’s perfection. That number became associated with the four universal elements, air, earth, water and fire, to which were added four qualities, dry, moist, cold and hot. The Hippocratic School added the four body humors, blood, phlegm, yellow bile and black bile, to the four universal elements and their qualities.
These humors were assumed to constitute the nature of the human body. The body is in a healthy state when the four humors are in equilibrium; diseases occur when one is reduced or in excess, or when it metastasizes, that is when it separates from the other humors and becomes confined to some part of the body [12]. Cancer was thought to be caused by an excess or sequestration of black bile [13, 14]. A number of practices aimed at expelling the harmful humor from the body, such as purging, bleeding and using emetics, are based on the humoral theory. As a child, I can recall that leeches were sold in pharmacies and that my grandmother used to apply cupping glasses on my back whenever I had a cold. The four humors were also linked to psychological characteristics and we still use such words as sanguine, phlegmatic, bilious and melancholic (from melan chole: black bile).
We owe the Latin word cancer to another Greek physician, Aulus Cornelius Celsus (30 BC-circa 38 AD), who practiced in Rome after Greece became part of the Roman Empire. His eight-volume treatise De Medicina, written in Latin, is an in-depth account of the medical and surgical knowledge from the time of Hippocrates. In his books, Celsus refers to several primary cancers and mentions the progression of cancer from an early tumor to an ulcerated one: “And generally the first stage is what the Greeks call cacoethes (malignant); then from that follows a carcinoma without ulceration; then ulceration, and from that a kind of wart [15]”. Celsus further commented that with the exception of the first stage, cancer is incurable, as recurrence occurs even after a scar has formed [15], adding that the distinction between potentially curable cancers from incurable cancers can only be learned with time and experience. De Medicina was published in Florence in 1478, becoming the first printed book of medicine [14].
The third Greek physician to achieve celebrity as an outstanding practitioner and writer was Claudius Galen (130 AD-200 AD). His medical and surgical knowledge and skills made him the appointed physician to the gladiators, and the physician of two Roman emperors. His short book De Tumoribus Praeter Naturam, On Tumors beyond Nature, is devoted to swellings with diverse causes, including cancer. Galen followed and emphasized Hippocrates’ humoral theory of cancer [14]. He considered two types of black bile, a milder form causing non-ulcerated cancer and another leading to ulceration: “When black bile attacks flesh, being biting it eats the surrounding skin and causes an ulcer; but when it is milder it causes cancer without ulceration [16]”. Note the wording: attacks, bites, eats; these and similar words have remained attached to this disease. Galen’s influence on medicine was considerable and his authoritative writings became dogma, to a large extent impeding medical progress during the Middle Ages.
Cancer treatment in Antiquity consisted of excision and cauterization with a hot iron of tumors deemed operable. For ulcerated cancer, ointments containing arsenic and vinegar and caustic pastes made of lime, arsenic, or various metals, including lead, copper, zinc or their salts, as well as soothing substances such as zinc oxide, cabbage or carrots mixed with honey, oil or other compounds, were applied as plasters [3, 17-20]. To ease pain, ointments made of poppy heads were used [17]. A number of other remedies, often complex mixtures made of minerals and various extracts of herbs, plants, trees, and even extracts from animals, were taken as infusions or used as external or internal applications [18-20]. It is difficult to assess the effectiveness of these medications, but zinc oxide applied to irritated skin is an effective soothing and anti-inflammatory compound, as every mother familiar with diaper rash can testify, and arsenic was still considered an effective caustic agent in the 18th century [17]. Similarly, mustard was used in the 16th and 17th century as a caustic and vesicant to treat cancer [17]; when I was a child, mustard poultices were still applied on the thorax as a lung decongestant and if care was not exercised, produced skin burns and blisters. However, the physicians of the time must have considered these remedies as palliative only, since potentially curable cancers were treated by non-medical means.
