A founding father of medical oncology, Emil J. Freireich, MD, died February 1, 2021, at age 93, in Houston, his home since 1965. Recognized as a pioneer in modern clinical cancer research, he leaves behind a monumental legacy.
Three prominent personality assets defined Dr. Freireich’s life and career: infinite optimism; the audacity to question established knowledge, dogmas, and convention; and unlimited, wild imagination. To paraphrase Robert Kennedy, instead of accepting things as they are and asking, “Why?” (and how they came to be), Dr. Freireich questioned conventions, rejected hopelessness, saw things that never were and asked, “Why not?” (and how can they be changed). He emphasized that all knowledge is contemporary, transitional, and very dynamic, knew that most of what we accept as medical truth today will be obsolete soon, and always asked how this knowledge could be improved or replaced. Fortunately for humanity, these three attributes, controversial at times, revolutionized cancer research and treatment and saved the lives of millions of patients.
Dr. Freireich was born in 1927 to Hungarian immigrants and lost his father when he was two years old. As he recounted in his 1997 oral history (preserved at the National Cancer Institute [NCI]), “People born in that era … lived through one of the greatest economic dislocations in the history of our species — the Great Depression of 1929… There was no work, no jobs, no money, and no food…we all grew up believing that the whole world was this jungle… We used to get beat up [and] robbed; we used to steal; we were hungry.” And yet, despite seemingly hopeless surroundings, he survived and remained an eternal optimist. From that optimism and drive, he grew to become one of the greatest innovators in cancer research.
“Humans cannot live without hope. Hopelessness is the greatest trauma a person has to suffer,” Dr. Freireich said. And it was hope that drove him, and what he consistently offered to his patients. To the mantra of “letting patients die with dignity,” he countered, “There is even greater dignity in fighting for one’s life.” He liked to show the cards he received every Christmas from patients who had been deemed hopeless but who were cured by one of his interventions. When Dr. Freireich heard that one of the MD Anderson Cancer Center faculty, Dr. John Benvenuto, was dying of pancreatic cancer in Tampa, he traveled to see him, paid $5,000 for the flight to Houston from his credit card (in 1986 insurance refused to cover medical travel for the terminally ill), and supervised his treatment. Dr. Benvenuto lived for another decade.
Dr. Freireich’s audacity led him to defy traditions and conventions and to antagonize the establishment. This caused him grief aplenty. According to the New York Times, his internship at Cook County Hospital in Chicago ended after a confrontation with a nurse who put his patient with heart failure in the “dying room” instead of keeping him under Dr. Freireich’s care. He was labeled a “troublemaker.” Dr. Freireich said he was almost fired three times during his NCI tenure (1955-1965) because of the controversies surrounding his then-considered “radical” work on platelets and on combination chemotherapy. Perhaps this was compounded by his forceful personality, unshakable belief in the foregone success of his endeavors, and direct, sometimes confrontational approach.
Dr. Vincent DeVita, who joined the NCI as a clinical associate in 1963, recalled that many of his peers “had been warned by their professors not to get too close to Dr. Freireich,” due to his reputation for being so outspoken. But Dr. DeVita later came to admire Dr. Freireich and was inspired to develop the well-known curative MOPP (mustargen, oncovin, procarbazine, prednisone) regimen for Hodgkin lymphoma.
At the dawn of medical cancer research, there were no guiding rules. Dr. Freireich created his own principles known as “Freireich’s Laws.” Witnessing the inexorable deaths of children with leukemia on the NCI ward, he started treating them with two-, then three-, and then four-drug chemotherapy combinations. His work was criticized as immoral and criminal, and he was reminded of Hippocrates’ statement, Primum non nocere (first do no harm), to which Dr. Freireich responded with his own Law No. 5 (the physician’s creed): “Primum non nocere fails to do the possible and the necessary. The physician’s admonition must clearly be: Do what can possibly be done, and, perhaps more important, do that which is necessary.” In essence, “First do no net harm,” as Dr. Daniel Sokol later clarified in a 2013 British Medical Journal article.
Dr. Freireich and his NCI colleagues conducted the first randomized trials in leukemia, and in the early days of cancer research, the control or standard-of-care arm delivered the expected terrible results. Dr. Freireich soon turned against this “gold standard” of research, arguing that in a disease with such dismal prognosis, the investigational treatment most often produced better results. In his view, there was no “equipoise” in depriving patients of a novel approach. A corollary to this was his rejection that a phase I study should only define toxicity. Instead, he insisted that these early-phase studies should also evaluate efficacy so that patient participation in clinical research was always for potential benefit, not merely the altruism of the desperate. Today we have several drugs approved based only on efficacy in phase I trials. He rejected the term “experimental therapy” (benefit only to the experimenter) in favor of “investigational therapy” (mutual benefit to the patient and the investigator), which led to Dr. Freireich’s Law No. 1 (clinical investigator’s creed), which states “The primary beneficiary of clinical research is the patient participating in that research,” and Dr. Freireich’s Law No. 6 — “The best patient care is clinical research.” He then collaborated with Drs. Edmund Gehan, Peter Thall, and Elihu Estey to develop statistical methodologies that evaluate treatment benefit, absent a randomized trial, using rigorously matched historical controls, multivariate analyses, Bayesian statistics, and others.
Dr. Freireich’s visionary research led to discoveries that helped pave the way for the cure of many cancers. In recognizing his work, many emphasize the two discoveries at the NCI: the role of platelet transfusions in stopping bleeding in patients with thrombocytopenia (and the invention, in collaboration with IBM engineer George Judson, of the first continuous-flow cell separator), and the development of the concept of multiagent chemotherapy that cured childhood acute lymphocytic leukemia (ALL) and later, other cancers.
His contributions during his 1965 to 2021 tenure at MD Anderson were as significant, if not more so. Dr. Freireich and Emil Frei III were recruited to this little-known “research and tumor institute” focused on cancer surgery and radiation, and established the Department of Developmental Therapeutics (DT), the first-ever large-scale entity whose mission was to create a comprehensive chemotherapy program. Recognizing the need for multidisciplinary approaches to discover innovative therapies, they recruited national and international leaders in hematology (Drs. Kenneth McCredie, Jeane Hester, Michael Keating, Bart Barlogie, Fernando Cabanillas, Karl Dickie, Axel Zander), oncology (Drs. Gabriel Hortobagyi, Robert Benjamin), infectious diseases (Dr. Gerald Bodey), immunology (Drs. Evan Hersh, Jordan Gutterman), pharmacology (Drs. Ti Li Loo, Dah Si Ho, David Farquhar, Benvenuto), biostatistics (Dr. Gehan) and basic research (Drs. William Plunkett, Walter Hittelman, Michael Siciliano, Priscilla and Grady Saunders), and dozens of others. Basic science and clinical research were melded to form one of the greatest clinical-translational research departments in the world. In this regard, Dr. Freireich was the first clinical-translational researcher, even before the discipline had a name.
At its peak, DT was described colorfully by some as a Tower of Babel, a mini United Nations, and a Grand Bazaar — a constellation of the most diverse group of cancer researchers who led much of the early research in cancer. Many of the early chemotherapy drugs such as cytarabine, adriamycin, and cisplatin were developed during this period, and subsequently became components of many curative regimens in cancer: cytarabine-anthracyclines in leukemia; CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in lymphoma; 5-fluorouracil-adriamycin-cyclophosphamide (FAC) in breast cancer; bleomycin-velban (and the later addition of cisplatin by Dr. Lawrence Einhorn, a DT fellow in 1972) in testicular cancer; and others.
After Dr. Bodey described the association between neutropenia and infections, he and Dr. Freireich conceived of using empiric antibiotics for fever and neutropenia (without waiting for positive cultures). This and platelet transfusions drastically reduced the two most common causes of death during cancer therapy, infections and bleeding, and allowed the safer use of intensive chemotherapy in hematologic and solid tumors and the implementation of stem cell transplantation (SCT).
Additionally, the invention of the blood cell separator (pheresis machine) by Dr. Freireich allowed not only platelet transfusions but also the collection of peripheral blood stem cells (originally reported by Dr. McCredie to circulate in the blood) for SCT. Before empiric antibiotics, Dr. Freireich also explored the value of separating white blood cells as therapy for infections and neutropenia. The early studies were mixed, but a more modern use of unirradiated white cell transfusions with growth factors administered to the donor and patient may revive the strategy for severe infections not responding to antibiotics (cellulitis, sino-orbital infections, typhlitis, enterocolitis, rectal abscesses), 60 years after the original work!
Training physician-scientists was one of Dr. Freireich’s priorities beginning with his earliest years at MD Anderson. He created a fellowship program in medical oncology even before it was a recognized board-certification specialty. He firmly believed in the need for clinician-scientists who not only worked in a laboratory but also delivered direct patient care. This was likely his greatest legacy as he trained and molded the thinking of several generations of oncologists, many of whom exported their experience to near and distant geographies, built new cancer research and treatment centers, upgraded the level of cancer care and research, and established their own legacies by helping hundreds of thousands of patients.
Dr. Freireich’s imagination, discoveries, and personality left no room for emotional neutrality, dividing people into those who loved him immensely and those who resented him, but who were still intrigued by his research and who ultimately came to recognize and admire his contributions. Friends and foes described him with hyperbole and with often contradictory sentiments: force of nature, enigmatic character, incredible charisma and magnetism, genius, visionary, innovator, exceptional, ahead of his time, great storyteller, harsh and critical, egotistical, eccentric, iconoclast, and a choice menu of unprintable words. He enjoyed his status as an outsider and as a “Texas cowboy,” often sporting in the 1960s to 70s cowboy hats and boots, which added eight inches to his already massive frame and perpetuated his image as an even larger than larger-than-life figure.
Freireich started the use of acronyms in cancer; he got a laugh when a Blood reviewer of his 1965 paper on POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) in ALL said, “The treatment they propose is a drastic one… There is also an irritating quality to the writing. The use of acronyms for drug combinations is amusing but seems an excessive effort for the results they report. POMP, BIKE, and VAMP are going to have the acceptance of RADAR and LASER or WAVES …they exhibit a devious talent inappropriate in a scientific report.” Little did the reviewer know this was only the beginning of a linguistic monster in cancer.
Freireich is the ultimate expression of the phrase, “I am MD Anderson.” His death leaves our institution and the world of cancer research diminished. Dr. Michael Keating, Freireich’s close friend, colleague, and world-renowned leukemia researcher said, “We were lucky to be observers and participants in his life — a life wonderfully led.” His was a life that began amidst suffering, but that was spent working to alleviate it.
