Remembering Emil J Freireich: Trailblazing pioneer and giant in cancer research
Authors: Hagop M. Kantarjian
Journal: American Journal of Hematology (2021)

A founding father of medical oncology, Emil J Freireich, M.D., died February 1, 2021, at age 93, in Houston, his home since 1965. Freireich, Gordon Zubrod, James Holland and Emil (Tom) Frei III, were among a dozen founders of medical cancer research, when it began in the early 1950's. Freireich was the "inaugural" leukemia researcher. In these early days, experts did not believe that cancer could be cured except with surgery and irradiation. In 1955, M. C. Li had shown that choriocarcinoma could be cured with methotrexate, but this was possible only because it was a tumor of the fetus, foreign or "allogeneic". But "syngeneic" tumors, they reasoned, were incurable. Freireich shattered this dogma by curing childhood acute lymphocytic leukemia (ALL) with multi-agent chemotherapy. Three personality traits were the guiding compasses of his life and medical career: infinite optimism, unlimited audacity, and boundless imagination. As Robert Kennedy once stated, instead of accepting things as they are and asking, "Why?" (and how they came to be), Freireich saw things that never were and asked, "Why not?" (and how can they be done). He stressed that all knowledge is contemporary, transitional and dynamic, and that most of what we accept as medical truth will be obsolete soon. He questioned incessantly how cancer knowledge could be improved or replaced. Fortunately for humanity, Freireich's genius and personality attributes, controversial at times, revolutionized cancer research and saved the lives of millions of people. The early life of Freireich illustrates his optimism. Born in 1927 to Hungarian immigrants, Freireich lost his father when he was 2. He recounts in his 1997 oral history the crushing hopelessness surrounding his early life: "People born in that era lived through one of the greatest economic dislocations in history, the Great Depression of 1929. There was no work, 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." Still, he survived and remained an eternal optimist. From that, 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," he said. When he joined the National Cancer Institute (NCI) in 1955, Freireich witnessed firsthand the hopeless fate of children with ALL on his wards. He then made his first two major discoveries, platelets transfusions and combination chemotherapy. When his colleagues questioned his work and reminded him that he should let the children" die in peace and with dignity", he responded: "There is greater dignity in fighting for one's life". He offered patients hope and often delivered on his promise with what others considered as medical miracles. He liked to show the Christmas cards he received from patients who had been declared hopeless by others, but were cured with one of his interventions. And he had great kindness. In 1986, when he knew that one of the MD Anderson faculty, John Benvenuto, was dying of pancreatic cancer, Freireich traveled to see him in Tampa, paid $5000 on his credit card for the air ambulance to Houston (insurance refused to cover medical travel for terminally ill) and supervised his treatment. Benvenuto lived for another decade. Two miracles qualify for sainthood in the church; should Freireich be then canonized? The second characteristic, audacity, caused him grief galore. He questioned conventional knowledge, traditions and dogmas. His internship at Cook County Hospital in Chicago ended following a confrontation with a nurse who judged his patient with heart failure to be terminal and put him in the "dying room". He was labeled a "troublemaker." He was almost fired three times during his tenure at the NCI (1955–1965) because of controversies surrounding his "radical" work. His unconventional research, combined with a forceful personality, strong belief in the ultimate success of his work, and at times unfiltered demeanor, resulted perhaps in some animosity and cost him political capital. Vincent DeVita, Freireich's friend and colleague, remembered that many at the NCI "had been warned by their professors not to get too close to Freireich". The NCI, they said, was a "good place to stay out of Vietnam but stay away from Freireich." Inspired by Freireich's work, DeVita developed the well-known curative MOPP regimen in Hodgkin disease. Freireich's audacity led him to promulgate what he named (in jest at the beginning) "Freireich's Laws". At the dawn of cancer research, there were no guiding principles, and his work on platelets and combination chemotherapy was criticized and labeled immoral and criminal by the establishment. He was reminded of the famous medical dictum, "Primum non nocere" (first do no harm; attributed to Hippocrates, but perhaps first said by Thomas Inman in 1860). Undeterred, Freireich responded with 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". Daniel Sokol eloquently formulated the new decree, "First do no net harm", in a 2013 editorial in the British Medical Journal. Audacity was what led Freireich to his first two discoveries at the NCI. It was then accepted that children with ALL were bleeding to death because they had "anticoagulants" in the blood, not because of low platelets. He first demonstrated the association between low platelet counts and bleeding and showed that bleeding could be stopped by transfusing fresh blood. When a hematology eminence of the time commented, after a presentation by Freireich, that his laboratory could not reproduce the findings, Freireich retorted: "My laboratory does it better" (this certainly did not gain him a new friend). In collaboration with George Judson, an IBM engineer, he invented the first continuous-flow cell separator (what we call now "pheresis machines") to isolate platelets. While platelet transfusions stopped bleeding, Freireich realized that children would still die unless he eradicated the leukemia. He then embarked on what was then considered a most daring endeavor (in hindsight, it seems of course so logical) – treating childhood ALL with two, then three, then four chemotherapy drugs, and then extending the treatment duration into an induction-consolidation-maintenance therapy. By curing childhood ALL, Freireich established a new principle: cancers are curable with chemotherapy. This concept was then tested and led to the cure of many cancers: Hodgkin's disease, lymphoma, breast, testicular, others. Audacity caused him to question the value of "randomized clinical trials" as the gold standard in cancer research. Freireich and his colleagues performed the first randomized trials in leukemia. At the time, the control arm delivered the anticipated poor results. Freireich proposed that, in a disease with a dismal prognosis, the investigational treatment was almost always better. He was concerned that patients in the control arm were not receiving, based on cumulative (Bayesian) knowledge, the best treatment. There was often no "equipoise". He argued that only when the control arm offered good results, for instance cure rates above 50%–60%, would it be tenable to consider randomized trials. Otis Brawley recalls Freireich reminding people that no phase 3 trials were needed to confirm that cisplatin worked in testicular cancer. He then joked that the "only reasonable phase 3 trial was a comparison of Coke versus Pepsi". Translation—only when in a land of plenty can one afford such luxury, but perhaps not when more people die than live. Freireich said," there is no need for randomized trials to know that parachutes and seatbelts help, and that excess alcohol and smoking harm". He also rejected the notion that a phase 1 study should only evaluate toxicity and insisted that it should analyze efficacy as well. Patient participation in such clinical research should always be for a potential benefit, not altruistic. Today we have several drugs approved based on efficacy in phase 1 studies. He did not like the term "experimental therapy" (benefits the experimenter) and favored "investigational therapy" (benefits the patient and the investigator). Freireich's Law No. 1 (Clinical Investigator's Creed) stated: "The primary beneficiary of clinical research is the patient participating in that research." Freireich's Law No. 6 stated: "The best patient care is clinical research." He then collaborated with Edmund Gehan and others to develop alternative statistical strategies that evaluate treatment benefit: rigorously matched historical controls, multivariate analyses, Bayesian statistics and others. Boundless imagination is what moved the needle in Freireich's research. While the original NCI discoveries are often mentioned as his major contributions, his most seminal breakthroughs happened during his 1965–2021 tenure at MD Anderson. When Freireich and Frei were recruited to MD Anderson, the institution was a little-known "Tumor and Research Institute" focused on cancer treatment with surgery and radiation. Freireich was tasked with starting a cancer research program for developmental therapeutics, or DT. This became the largest and most diverse program of its kind in the world. Freireich and Frei were the magnets that attracted hundreds of like-minded researchers from near and far. In 1978, as a fourth-year medical student, I applied for a 4-month elective rotation to the two established cancer centers in the US, Memorial Sloan Kettering and MD Anderson. Memorial rejected me immediately. Freireich accepted me immediately, "sans voir" (as they say in poker). I thought it was because my CV (less than half-a page with a lot of embellishments) and letters of recommendation impressed him. I later realized that Freireich followed a line from Georges Brassens's poetry: "Embrasse-les tous, Dieu reconnaitra le sien" (Embrace them all, God will sort his own). He accepted all and molded us into the best cancer researchers we could ever become. Fernando Cabanillas recalls: "When Freireich welcomed the new fellows in July 1974, he said that all of us in the room had been selected because we were geniuses. I was so naive that I believed him. I did not consider myself a genius and was even worried that I had been accepted through a bureaucratic glitch that would soon be discovered. Nevertheless, he made us all feel important and capable of anything, which I think was what he wanted". After I landed in Houston on Thanksgiving 1978, and started my rotation at MD Anderson, I was star-struck to be amid cancer celebrities: Kenneth McCredie, Gerald Bodey, Evan Hersh, Jordan Gutterman, Robert Benjamin, Gabriel Hortobagyi, Michael Keating, Bart Barlogie, and Fernando Cabanillas. But DT people did not behave like celebrities. It was more like a Grand Bazaar, a Wild West, a constellation of cacophonies and opposing views espoused by brilliant researchers with big egos. Meetings would get tense as many opinions were invented, proposed, shared, some even shouted. I became concerned about the wisdom of having left the safety of Lebanon and its civil war for the DT danger zone. Or "Dangerous Territory" as the fellows used to refer to it behind Freireich's back. Many of the early chemotherapy drugs such as cytarabine, doxorubicin and cisplatin were developed during this DT period, and became components of many curative regimens in cancer: cytarabine-anthracyclines in leukemia; CHOP in lymphoma; 5-fluorouracil-Adriamycin-cyclophosphamide (FAC) in breast cancer; bleomycin-velban (and the later addition of cisplatin by Lawrence Einhorn, a DT fellow in 1972) in testicular cancer; and others. When Bodey described the association between neutropenia and infections, he and Freireich started the concept of empiric antibiotics for fever and neutropenia (without waiting for positive cultures). Platelet transfusions and empiric antibiotics drastically reduced the two 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. Also, with McCredie's discovery that stem cells circulated in peripheral blood, the pheresis machines has a new use, collection of peripheral stem cells for transplantation. Before empiric antibiotics, Freireich also explored the value of separating white blood cells as therapy for infections and neutropenia. The early studies were mixed, because white cells were irradiated (fear for engraftment and production of graft-versus-host disease; later proven incorrect by Freireich in—shockingly– a randomized study published in Cancer in 2010), and because the trials explored their use as prophylaxis. 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, sinus-orbital infections, typhlitis, enterocolitis, rectal abscesses)— 60 years after the original work. One of Freireich's priorities at MD Anderson was training physician-scientists. In 1966, he created a fellowship program in medical oncology before it was a recognized board-certification specialty. He believed in the need for clinician-scientists to combine basic and clinical research, and to translate quickly their laboratory discoveries into meaningful patient care. He was the first clinical-translational researcher, long before the discipline had a name. This was likely one of his greatest and most enduring legacies, as he trained several generations of oncologists, many of whom took their experiences to near and distant places, built new cancer research and treatment centers, improved cancer care in their own homes, and helped cure hundreds of thousands of patients with cancer. Freireich started the use of abbreviations (acronyms) to describe regimens in cancer. He enjoyed and shared this Blood review of his 1965 paper on POMP in ALL: "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." Freireich's imagination, discoveries and personality left little room for emotional neutrality. They divided people into those who loved him unconditionally and those who resented him, but were still intrigued by his research, and ultimately recognized and admired his contributions. His demeanor made for great material, and hundreds of his mentees would tell stories, true or exaggerated, about encounters with Freireich. We all have our own stories and anecdotes. As befits his legend, they will be amplified and distorted to become more fables than true stories. But is this not always the case with the great? Freireich was a third parent to many of us, and like all children, each of the hundreds of us claimed emphatically to be Freireich's most loved. And he did make everyone who worked with him feel as though we were his single most important and favorite person. (For the record, I was. ☺) Friends and foes described him in colorful terms: force of nature, enigmatic, charismatic, genius, visionary, innovator, exceptional, ahead of his time, great storyteller; but also loud, overbearing, harsh and critical, egotistical, iconoclast and a choice menu of unprintable words. He was, at times, politically incorrect, but just to stir interesting conversations. In my first meeting with him, he asked me if I was a terrorist (perhaps misled by the excessive production and poor distribution of pitch-black head and facial hair, an Armenian gift). In her first one-on-one interview for fellowship in 1985, a slightly intimidated Susan O'Brien wanted to elaborate on her educational pedigree, qualifications, accomplishments and aspirations. Freireich's first question was: "Are you a feminist?" She was lucky that "Feminazi" was not in use till 1991. In remembering Freireich, I hope I have not glossed over his flaws. He was perhaps not a saint, but he was certainly one of the great ones, a prince among oncologists. I imagine our Creator now a bit ruffled with Freireich arguing how He might consider some changes in His Creation. Not Applicable Appendix S1: Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.