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An Homage to Two Explorers of Uncharted Cancer Waters

2021; AlphaMed Press; Volume: 26; Issue: 4 Linguagem: Inglês

10.1002/onco.13731

1549-490X

Bruce A. Chabner, Vincent T. DeVita, Martin J. Murphy,

Neutropenia and Cancer Infections

In recent weeks oncology lost two great physician-scientist-leaders, Emil J Freireich and Joseph V. Simone [1, 2]. Comprehensive biographies of both men have appeared (https://ascopost.com/news/february-2021/emil-j-freireich-md-dies-at-93/ and https://blogs.stjude.org/progress/joseph-v-simone-st-jude/) [3, 4]. As a friend and associate of both men, and as a witness and participant in that remarkable period when cancer treatment became a curative reality, I have very vivid and fond memories of both. As it happens, both J (“J” stood for no name—it was just an initial) and Joe came from Chicago, where they were raised in immigrant communities. J's parents immigrated in the 1920s from Hungary. His father died when he was just 2, and he was raised by his mother in relative poverty, but he proved to be a remarkable student, finishing medical school at the University of Illinois at age 22. J pursued further training in Boston at Boston University's Massachusetts Memorial Hospital in the Hematology Department and, in 1955, was recruited to join the National Cancer Institute (NCI) as a junior investigator under Emil J. Frei (Tom). J recalled his first visit to NCI, where he found Tom's name on the door, and thought perhaps they had mistakenly truncated his name, Emil J Freireich. He walked into the office and found a tall string bean sitting at the desk. It was Frei's office. The combination of Frei and Freireich was sensational—the pair creating the first curative multidrug protocols for childhood leukemia and J solving the vexing problem of hemorrhagic deaths with his invention of platelet transfusion made possible by pheresis technology. J witnessed futile attempts to treat sepsis in neutropenic patients and reasoned that early introduction of multidrug broad-spectrum antibiotics in febrile neutropenia could save children during this crucial interval. Together, Frei and Freireich created a format for intensive, and curative, chemotherapy of this disease. At the same time, Don Pinkel and, later, Joe Simone, furthered this work with improved chemotherapy, CNS prophylaxis, and large randomized trials at St. Jude. As described below by Vince DeVita (Frei–Freireich fellow at NCI, 1963–1965), Freireich was forever bombastic, outspoken, and impatiently critical of foolish thinking and cautious skepticism. He knew that the journey to cure required making drastic changes and taking chances. At the same time, he was a warm and supportive mentor and friend to many of the future leaders of oncology as they served in the training programs at NCI and, later, at MD Anderson, where he settled for the remainder of his career in 1965. The list of trainees graduating from his Developmental Therapeutics fellowship at MD Anderson is a virtual Who's Who in Oncology (e.g., Kantarjian, Hortobágyi, McCredie). I visited him several times there and always enjoyed his wide smile, his laugh that shook his mighty torso, and his eloquence. His legacy is the premier leukemia service at MD Anderson, which he nurtured and advised through his later years. Distilling one lesson from my years of friendship with J, I owe the most to those like J and like DeVita and George Canellos who challenged my assumptions and my thinking. In contrast to J, Joe Simone was the quintessential diplomat, organizer, and unifier, in addition to his great ability as a clinical researcher. He brought St. Jude Children's Research Hospital to the highest level of clinical investigation in childhood malignancy during his 25 years as a clinical investigation and 9-year tenure as Director of St. Jude, from 1983 to 1992. Not only was he a significant contributor to the development of total therapy for childhood leukemia, but he recruited a number of first-rate clinical investigators (Hon-Chi Pui, William Evans) and renowned basic scientists (Chuck Sherr, Jim Ihle, and Peter Doherty), and created a billion dollar basic research program. It would be impossible to describe his many contributions as an advisor to NCI and other cancer centers. I personally worked closely with him when he served as a member of the Board of Scientific Counselors of the Division of Cancer Treatment at NCI. We often joked that his family, the Simones, and my mother's family, the Simons, probably shared a common ancestor somewhere in the Mediterranean. His wisdom and stature were immensely valuable in resolving so many issues: giving up a failing investment in neutron therapy, supporting immunotherapy, building an effective pediatric oncology group, supporting natural product research that led to paclitaxel, and establishing comprehensive auditing for NCI-sponsored trials. During his later years at Memorial Sloan Kettering and the Huntsman Cancer Institute, he strengthened the training programs and faculty at these institutions. He was famous for his book of Simone's Maxims, still in print, which advised young academics how to negotiate the treacherous waters of academic medicine [5]. While he reflected that “institutions don't love you back,” certainly the people he mentored and befriended reciprocated that love. Although the contributions of these early oncologists may seem distant in years, they should not be forgotten. We live within the culture of deep commitment to research and devotion to discovery that they created. I came to the NCI as a fellow with Bob Young in 1967, and very much felt embedded in a culture established by Freireich and Frei, and carried forward by their trainees. That culture continues today in the work of the brilliant younger physician-scientists who have carried our field into the molecular age. Without them, without the Freis and Freireichs, the Simones and Pinkels, without DeVita and Canellos and the many other people they trained and mentored, the current practice of oncology would still be sailing to terra incognita. Elizabeth (Vince's daughter and co-author of his book, The Death of Cancer [1]) expresses my feeling about Jay well. After our book was published, I sent Jay a copy, somewhat fearful about how he might take the stories (about J's escapades at NCI). I asked that he read it through to the end, as he was the hero of the book—an inspiration. To me, the stories explained his intensity in work and play. He wrote me a very nice letter saying he enjoyed the book and the stories, and it would occupy an important place on his bookshelf. Deep down, he was a kind person. When he thought you needed adjustment, he could get excited and poke you in the chest with his bony index finger for emphasis. I can still feel the pokes! He was passionate and had the courage of his convictions. He was a great mentor to me. I owe him much. So do a lot of little people who grew up to be big people because of him. Rest In Peace Jay. May a band of little angels sing you to your rest. Martin Murphy joined St. Jude's as an assistant member 6 years after Joe was recruited and was immediately befriended by Joe. Now deputy editor of The Oncologist, Marty and Joe remained friends for the next 4 and half decades. Marty recalls: St. Jude's legendary founding director, Donald Pinkel, recruited Joe in 1967 by saying, “You must have a Moby Dick to chase.” Don had already identified pediatric leukemia as his Moby Dick, but he needed a special leader to recruit, train, and retain like-minded pediatricians. He needed Joe. And it wasn't long before Don promoted Joe to director of St. Jude's signature Leukemia Program. Mind you, it was not seen by many extramural to St. Jude as an enviable promotion, given that pediatric leukemia was at that time considered rarely curable. Indeed, pediatricians who sought to change its inevitable outcome by giving “poisonous chemicals” to children were pilloried at several national meetings, Joe and Don among them. Acute lymphocytic leukemia of childhood was to become their Moby Dick, with Don clearly cast in the role of Captain Ahab and Joe playing half a dozen other crewmembers on St. Jude's Pequod. Most especially, Joe was cast as Ishmael, the man aboard who held much of it together. Joe narrated what was happening and, with a weather eye to leeward, foretold storms that inevitably brewed in the unchartered seas of chemo- and radiation therapy. Joe kept many of us, me especially, out of harm's way. Building on the combination therapies developed by Freireich and Frei at NCI, the St. Jude team added the crucial CNS prophylaxis consolidation and maintenance therapies, and other refinements derived from beautifully sequenced trials that led to the current 90% cure rate of childhood ALL. The good ship St. Jude was joined in convoy to cure by other vessels from major pediatric oncology centers in that voyage. The years 1973–1975 were formative in my career, made more so by Joe's sage advice and fraternal counsel always proffered with honesty and a sense of humor. His outsized impact was on St. Jude's crew who together harpooned Moby Dick. In so doing, Joe helped change the course of cancer history, as many of his little patients lived to make grandparents out of their parents.