THERAPEUTIC REVOLUTION The History of Medical Oncology from Early Days to the Creation of the Subspecialty

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.

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.

Medical research carried out during World War II influenced the development of cancer medicine. First, classified research on mustard gas led to the discovery that nitrogen mustard produced tumor regressions in advanced lymphomas. This event marked the dawn of modern cancer chemotherapy. Secondly, the supply of quinine, virtually the sole treatment for malaria, came to a halt after the conquest of Indonesia. As a result, there were more casualties caused by malaria than by combat among American troops fighting in areas where malaria was endemic. To address this critical situation, an extensive cooperative program involving outstanding experimental and clinical investigators was undertaken in the United States to find drugs other than quinine that would be active against malaria. Within a short time, the problem was solved. After the war, several members of the antimalarial program joined the National Institutes of Health. One of them, Dr. Charles Gordon Zubrod, would bring to medical oncology the same vision and organization that made the antimalarial war program a unique success.

Dr. Lucy Wills, a British hematologist, worked in India on “pernicious anemia of pregnancy” which was later found to be caused by folic acid deficiency. Dr. Yellapragada Subbarow synthesized that vitamin, as well as analogues that blocked its activities, including the drugs aminopterin and methotrexate. Aminopterin, first used by Dr. Sidney Farber, induced complete remissions in children with acute lymphocytic leukemia. Dr. Cornelius P. Rhoads was the U.S. Army Chief of the Medical Division of the Chemical Warfare Service during World War II. When the war ended, an outstanding group of scientists and clinicians who had served under him went on to play a major role in the development of medical oncology. Three of them, Doctors David Karnofsky, Frederick Philips, and Chester C. Stock, as well as Dr. Joseph H. Burchenal, joined Rhoads at the Memorial Hospital and Sloan-Kettering Institute for Cancer Research. The Memorial group developed a broad-scope cancer chemotherapy program that included screening, pharmacology, clinical investigation of chemotherapeutic agents and liaison with the pharmaceutical industry. During those years, two other important anticancer drugs were synthesized: cortisone by Dr. Edward C. Kendall and Tadeusz Reichstein, and 6- mercaptopurine by Doctors George H. Hitchings and Gertrude B. Elion. These scientists received the Nobel Prize in Physiology or Medicine for their achievements.

In 1953, the United States National Institutes, including the National Cancer Institute, were assembled in Bethesda. In 1955, a National Cancer Chemotherapy Program was established and scientific panels were formed with the participation of basic and clinical scientists and statisticians. An extensive experimental and clinical drug development program was initiated at the National Cancer Institute. Animal screening models predictive of anticancer drug activity were studied and criteria for preclinical toxicology and activity were developed. Important concepts emerged from experimental studies that influenced cancer therapy, including the dose-schedule and first-order kinetics principles, and the effects of anticancer agents on proliferating and resting cells. Under the leadership of Dr. Zubrod, the activities of a triumvirate of clinical scientists, Doctors Frei, Freireich and Holland, initially focussed on the treatment of acute leukemia, following up on Holland’s innovative use of a two-drug combination.

During the 1950s and early 1960s, several principles of chemotherapy were established, principally from methodical studies in childhood acute lymphocytic leukemia carried out within the setting of cooperative oncology groups. Combination chemotherapy, first initiated at the National Cancer Institute, led to a protocol comparing two drugs versus one; the results showed that two drugs given together were better than their sequential administration. The dose-schedule principle and first-order kinetic action of chemotherapeutic drugs were successfully studied in the clinic. A leap forward occurred with the demonstration that the effects of new chemotherapeutic agents could be tested in patients in clinical remission. Imaginative study designs were conceived leading to the identification of different phases of therapy: induction, maintenance and periodic reinduction. A continuous-flow blood cell separator was developed; granulocye and platelet transfusions were used to effectively reduce death from infections and hemorrhages; methods of treating meningeal leukemia became available. With these advances, long-term duration of unmaintained remission was seen in children with acute lymphocytic leukemia. Also, for the first time, the cure of a metastatic solid tumor in human, choriocarcinoma, was achieved.

Cooperative oncology groups were formed by the Cancer Chemotherapy National Service Center to test on humans promising chemotherapeutic drugs that were coming through the screening program. Patients from several institutions were pooled to shorten the time required to test new compounds against various malignancies, establish standards and objective criteria for diagnosis, patient selection, treatment and measurement of effect, and ensure statistically valid study designs and data analyses. The different phases of clinical investigation of malignant tumors were created: Phase I to establish the maximal tolerated dose of the new agent, its toxicity and pattern of reversibility; Phase II to look for activity in a broad spectrum of malignancies, which required the elaboration of objective criteria for therapeutic response; and Phase III to determine the efficacy and safety of the new drug in the specific cancer sites where activity had been observed in a Phase II study.

The principles of combination chemotherapy to overcome drug resistance and the use of high intermittent dosage to achieve maximal therapeutic benefits, first learned from studies in childhood acute lymphocytic leukemia, were applied to other hematologic malignancies and to solid tumors. As new drugs that were active against specific malignancies became available, they were tested in combination with other agents. Drugs with different mechanisms of action and no overlapping toxicity were preferentially selected for combination chemotherapy. Cures were achieved in Hodgkin’s disease, testicular cancer and Burkitt’s lymphoma, as well as improved survival in non-Hodgkin’s lymphomas. These major successes occurred in tumors characterized by a relatively rapid proliferating growth rates and were not paralleled by similar results in cancers with slower growth rates.

The growth rates of solid tumors in experimental animals and in humans were found to be exponential during their observable lifetime. It was concluded that cancer develops over a long clinically undetectable phase, during which the probability of occurrence of metastases is high. Solid tumors became viewed as frequently disseminated at the time of clinical diagnosis, thus requiring a systemic therapeutic approach in addition to the traditional loco-regional approaches offered by surgery or radiation therapy. However, studies in experimental animal models in which tumor growth can be measured over a wide range of doubling times have shown that solid tumor growth rates best fit a Gompertz function, in which the tumor doubling times continuously increase with increasing tumor size. Subsequent studies of the dynamics of tumor growth revealed that tumors are composed of proliferative and non-proliferative compartments, the latter consisting of cells that are able to proliferate again and cells lacking this capacity. In addition to therapeutic implications drawn from the Gompertz and cell-compartment models, experimental tumors characterized by a Gompertzian growth were added to the in vivo systems used to screen for drug activity.

In the 1950s and 1960s, the treatment of metastatic breast cancer in women consisted of hormonal ablative or additive procedures. However, no tests were available to predict patients’ response; as a result, about 60% to 70% of the women who underwent these endocrine procedures failed to respond. The discovery of the estrogen receptor enabled clinicians to select those women with breast cancer most likely to respond to hormonal procedures. Response to endocrine therapy occurred in about 60% of women with estrogen receptor rich tumors, as opposed to 8% in women with estrogen receptor poor tumors. Of added importance, assay of the estrogen receptor in the primary breast tumor was found to be predictive of response to endocrine therapy in women who subsequently developed disease recurrence. Tamoxifen, an anti-estrogenic compound synthesized in Great Britain, inhibits the binding of estrogen to the estrogen receptor. Tamoxifen underwent extensive fundamental and clinical investigations and became the standard form of endocrine therapy for breast cancer for over a quarter of a century.

In the early 1960s, breast cancer was considered to be poorly responsive to chemotherapy. However, several agents, in particular methotrexate, vincristine, 5- fluorouracil, cyclophosphamide, an alkylating agent synthesized in Germany, and prednisone were found to be active in women with metastatic breast cancer. These five drugs were then used in advanced breast cancer in a combination referred to as the “Cooper regimen” that triggered a number of studies using quadruple and quintuple chemotherapeutic drug combinations which induced response rates superior to therapy with single agents. These results led to the integration of combination chemotherapy into a combined modality approach, epitomized by modern ʻadjuvantʼ chemotherapy. A first randomized study comparing long-term postoperative single drug chemotherapy to a placebo led to improved survival in a subset of patients. Superior results were subsequently achieved with postoperative combination chemotherapy. The historical development of these approaches is described.

The chemotherapy of solid tumors followed the path opened by breast cancer: the use of active single agents combined for greater effectiveness in advanced disease and for their potential role in combined modality regimens. By the end of the 1960s, over 20 chemotherapeutic drugs effective against various malignancies were available to investigate these approaches. The use of combination chemotherapy in epithelial ovarian cancer, small cell lung cancer and osteogenic sarcoma showed improved response rates and duration of remission compared to previously used single drugs. Postoperative combination chemotherapy improved the survival of patients with osteogenic sarcomas.

Several innovations of the 1960s and 1970s influenced the future development of medical oncology. The Goldie-Coldman mathematical model related drug sensitivity to chemotherapy to the spontaneous mutation rate of malignant cells towards drug resistance. It added a new dimension to the scientific evidence for primary systemic therapy of cancer (neoadjuvant), an approach first investigated in osteogenic sarcoma and breast cancer that brought a novel orientation to the treatment of solid tumors. The Norton-Simon mathematical model drew attention to the Gompertzian kinetics of solid tumor growth and to the inference that chemotherapy needed to be intensified after achieving a complete response. The finding that dihydrotestosterone is the active form of testosterone in the prostate and the discovery of the nuclear androgen receptor led investigators to study the basis of progression of prostate cancer to androgen independence; from this research emerged the concept of intermittent androgen suppression for the treatment of prostate cancer. The concept of “total pain”, with its physical, emotional, social and spiritual aspects, and the emergence of palliative care and psycho-oncology, opened an entirely new era of cancer care.

Before the subspecialty of medical oncology was established, a few internists and endocrinologists had started projects devoted to the treatment of cancer patients; they also played a crucial role in the creation of the American Society of Clinical Oncology. Medical oncology became a subspecialty under the American Board of Internal Medicine (ABIM) through the persistent efforts of Dr. Byrl J. Kennedy whose key contributions to this endeavor are acknowledged by all. A Subspecialty Examination Committee on Medical Oncology was appointed to prepare guidelines for training and accreditation in this field and to prepare questions for the first examination. On October 16, 1973, 351 candidates passed the examination: the first cohort of certified medical oncologists.