The following is a foreword to a previously unavailable memoir by Charles Gordon Zubrod. The memoir is available for download here.
The Cancer History Project finds and publishes Zubrod’s autobiography
In histories of oncology, Charles Gordon Zubrod is a name that flashes by quickly, someone who did something important a long time ago.
Most likely, a foggy recognition is triggered by the Zubrod performance score, which measures how a patient is doing, with the 0 score that stands for experiencing no symptoms, through progression of disease, to 5—death.
Alas, Zubrod doesn’t always get credit for the Zubrod scale. You may also have heard this easy-to-use scale—accepted pretty much universally—referred to as the ECOG scale and, with slight modifications, the WHO scale.
Doctors who cite the Zubrod scale are showing their age.
Zubrod is sometimes remembered as the organizer, enabler and pacifier who managed to shepherd an unruly bunch of NCI scientists—particularly Emil “Tom” Frei III and Emil Freireich—through a wild ride that demonstrated the efficacy of chemotherapy in the treatment of childhood acute leukemia, resulting in the first long-term remissions of this disease.
Oncology is a young field, and those who saw its beginnings will tell you that Zubrod was more than a masterful bureaucrat. He was a visionary. A panorama unfolded in his mind. Big scientific structures clicked in like puzzle pieces with big structures of policy, and—this is very important—religion.
On Oct. 1, 1954, when Zubrod reported to work at a place then known pejoratively as the National Mouse Cancer Institute, a new area of medicine was being created, and Zubrod was so strategically placed, so knowledgeable, and so skilled in the art of politics that his vision ended up being embedded in the foundations of cancer research.
Write down the names of giants upon whose shoulders modern oncology stands. Virchow, Coley, Halsted, Huggins, Watson and Crick are probably on your list; Zubrod probably isn’t.
- He established the cancer clinical trials cooperative group system, beginning with the Acute Leukemia Group B, which was started with James Holland.
- He started a program to recruit clinical associates to NCI.
- He founded the NCI Leukemia Service and hired Frei and Freireich to run it and develop treatments for the disease.
- He developed quantitative methods that remain in use today in clinical trials and cancer treatment, including the phase I, II, and III system, endpoint measurements, the Zubrod scale, and flow sheets.
- He founded the NCI virus research program.
- He organized and defended NCI’s drug development program.
In a nutshell, Zubrod, a doctor educated at a time when the word “chemotherapy” denoted antibiotics, led an unruly bunch of much younger physicians to success in chemotherapy—leading to wide development and testing of chemotherapy, and increased public excitement about cancer research, resulting in substantial increases in federal funding for cancer research.
In a recent conversation, we challenged former NCI Director Richard Klausner to imagine cancer research without Zubrod.
Can you imagine it, Rick?
Klausner, who is not known for monosyllabic answers, responded with a pause and an elegant “No.”
If you wish to engage in the game of deconstructing history, pulling out threads and imagining what-ifs, try to pull out the thread called Charles Gordon Zubrod, and you will lose the initial successes in chemotherapy and the spirit of elation among scientists, philanthropists and politicians that resulted in the signing of the National Cancer Act of 1971.
No Zubrod, no path-breaking treatments, no National Cancer Act. To understand Charles Gordon Zubrod is to understand cancer history in a new way.
Why has so little been said about Zubrod?
Quotes in Zubrod’s obit in The Cancer Letter in 1999, offer insight:
- “He would give me credit or others credit that he deserved,” said Frei, then physician-in-chief emeritus, Dana-Farber Cancer Institute, and the Richard and Susan Smith Distinguished Professor of Medicine, Harvard Medical School. “He rarely put his name on papers.”
- “He was self-effacing,” said Nathaniel Berlin, former deputy director, Sylvester Comprehensive Cancer Center, University of Miami, who succeeded Zubrod as NCI clinical director. “He let many colleagues take credit for what he did. He was a generous man.”
- “He was quiet. He didn’t get enough credit, but he was a strong person behind the scenes,” said Vincent DeVita, then director of the Yale Cancer Center, who became the director of the Division of Cancer Treatment when Zubrod left NCI in 1974. “All of us owe him a great deal.”
- “His name wasn’t on the papers, but those of us involved in the system afterwards recognized that he was instrumental,” said Bruce Chabner, clinical director, Massachusetts General Hospital Cancer Center, who succeeded DeVita as the DCT director.
Zubrod’s creativity was boundless, and he took risks, Freireich said.
“Oh my God, if you tried to do that in 1997, they’d lock you up like you were insane, you know, there’s no Gordon Zubrod defending us any more. But in that day, in that age, Zubrod said, ‘Sounds crazy. Let’s do it,’” Freireich reflected in an oral history years later.
Zubrod was the kind of man who would happily spend unlimited time with a reporter, making sure that nuance gets through the skull and onto the page.
Sometime circa 1973, journalist Jerry Boyd, the founder of The Cancer Letter, needed guidance on a story about a new chemotherapy drug he had heard described at an NCI meeting.
To get straight answers, Boyd leafed through the White Pages, found the home phone number of C. Gordon Zubrod at 100 Oxford Street in Chevy Chase, Maryland, and dialed the number.
“He cut off my apology for calling him at night, at home, and insisted that I should call him any time I have any questions at all about cancer treatment,” Boyd recalled later (The Cancer Letter, Sept. 27, 2019). “Many of my questions were elementary, and I thought perhaps stupid. But Gordon very kindly and without any patronizing explained and answered in ways I could understand.”
After becoming a full-fledged luminary, Zubrod’s one-time protege Frei liked to join young faculty members for lunch at the cafeteria at Dana-Farber. The place was quite small—small enough to require only one cafeteria.
In the 1980s and 1990s, roughly once a week, Frei would spot young docs around a table, settle his lanky frame into a chair and start asking provocative questions.
“It might be something like, ‘Have you ever thought about why cells die?’” recalls Daniel Hayes, now a breast cancer expert at the University of Michigan.
This would have been a fantastic, cutting-edge question at the time, as the concept of apoptosis was just starting to be applied in oncology.
Alternatively, Frei could ask something like, “Do you think there is a group of cells at the core of a cancer mass that seem to be resistant to the therapy, even though the outer cells respond, which is why we see responses, but ultimately the cancers grow back, and then respond to the next therapy, and then grow back again?”
Also a great question, since this was long before the concept of tumor stem cells was popular.
At one of these lunch chats, Hayes asked Frei a question about Nobel Prizes: “Dr. Frei, if you could give the Nobel Prize to anyone in our field, but you can’t give it to yourself, whom would you choose?”
This was roughly after Michael Bishop and Harold Varmus won a Nobel Prize (1989), but before Donnal Thomas had won his in 1990.
“I figured Dr. Frei would mention someone related to oncogenes, or maybe Bernie Fisher for all he had done,” Hayes said. “Dr. Frei thought for a moment, and it was clear he was thinking ‘I think it should be me,’—although he would never have said that, just to be clear. And then said, ‘Gordon Zubrod, for all he did to establish combination chemotherapy.’
“What Dr. Frei was really saying is that Dr. Zubrod had brought together Drs. Freireich, Frei, and before them, Jim Holland, who, together, proposed combination chemotherapy, leading to the first chemotherapy-induced cures.”
Clearly, Zubrod didn’t seek recognition. Even this memoir, which we have the honor to publish as the foundational document of the Cancer History Project, wasn’t intended for mass publication. It’s not a trade book on which a New York publisher could ever make money. It’s not an academic history suitable for a conventional academic imprint.
Zubrod tells his family: this is how I came about, this is what I have learned, and this is how I learned it. And, importantly, this is what I believe. Outsiders weren’t among this book’s intended audience, so it makes it all the more fun to learn about the station wagons Mrs. Zubrod—Kay—drove to ferry the couple’s five children, and about her “double kitchen,” and the yellow Chambers gas range at the house in Chevy Chase.
Alan Rabson, an NCI pathologist who had been at the institute for two years prior to Zubrod’s arrival, lent The Cancer Letter his cherished autographed copy of Zubrod’s privately published tome. Rabson thought we needed it to write a proper obit for his friend.
Al was a gentle man, but it was clear that failure to return his copy within days would have resulted in a kneecapping.
This book’s title—Stairway of Surprise—comes from Ralph Waldo Emerson:
Pass in, pass in, the angels say,
In to the upper doors;
Nor count compartments of the floors,
But mount to Paradise
By the stairway of surprise.
A reader may be tempted to type the word “stairway” into the search bar of this manuscript and explore the importance of this imagery to the author. To the rest of us, this memoir is important because Zubrod is important. As we began the Cancer History Project, we asked the Zubrod family’s permission to make this illuminating book available to everyone in oncology.
Zubrod was born in 1914 in Brooklyn, NY, the son of a stockbroker. His mother died of pneumococcal pneumonia when he was eight. Growing up in Baldwin, NY, Zubrod’s main interest was sports, until illness with a bacterial pneumonia ended his athletic ambitions and left him with myopia, and, after a two-week hospital stay, a fascination with hospital life.
We see Zubrod as a devout Roman Catholic. He was a “daily communicant,” i.e. he went to Mass every day.
Zubrod went to high school at Georgetown Prep, a Jesuit school in Bethesda, Maryland, and later The College of the Holy Cross, also a Jesuit institution.
The Jesuits, the Society of Jesus, pride themselves on teaching students to be “men for others,” and teaching not what to think but how to think. Much of what Zubrod did was in the Jesuit tradition. It involved putting tremendous organization into the asking of every question, and questioning the validity of every finding.
We see that when Zubrod moved from one city to another to a new job, he always looked for a house he and Kay liked, and then checked out the parish church and school before buying. He once passed on a beautiful house because the local parochial school did not meet the needs of their children.
The names of priests appear alongside the names of Zubrod’s scientific colleagues, mentors, and students.
On these pages, whenever bad things happen, Zubrod doesn’t bemoan bad luck. Instead, he discerns the desire of the Holy Spirit and accepts it as such. When good things happen, or when he creates something useful, he attributes this to the work of the Holy Spirit as well.
Zubrod’s education was almost thwarted. When the Great Depression hit, his family couldn’t afford tuition, and he dropped out of Holy Cross. Luckily, the college president ordered him to return.
Zubrod received a medical degree from Columbia University College of Physicians & Surgeons in 1940, and he interned at Central Islip State Hospital in New Jersey, Jersey City Hospital, and Presbyterian Hospital in New York. At Presbyterian, he worked with Michael Heidelberger, the pioneer of quantitative immunology, in research on pneumonia.
In 1943, Zubrod was recruited and subsequently drafted into military service. He spent the war at Goldwater Hospital, working in the malaria program. Clinical trials were conducted on patients with central nervous system syphilis, who were given malaria to induce fever, which was then believed to be the only successful treatment for syphilis, Zubrod wrote.
“We aimed at giving each patient a hundred hours of fever above 103 degrees Fahrenheit, but this much continuous fever was debilitating, so [James A.] Shannon’s strategy called for interrupting the malaria induced fever by drug administration after four days of fever,” Zubrod writes.
This allowed for testing the drugs atabrine and quinine. Pharmacologic and clinical studies then produced superior drugs for malaria, chloroquine and pamaquine, he writes.
Nearly 80 years later, these drugs are still in use to treat malaria.
In August 1945, Zubrod’s mentor Shannon, a nephrologist who would later direct NIH, urged him to take two weeks off, something he hadn’t done in two years. Shannon suggested a stay at the Mt. Desert Island Biological Laboratory (MDIBL) in Salsbury Cove, Maine.
Here is Zubrod’s description of the lab and its traditions:
“The Laboratory was open only during the summer, and the scientists and their families began to arrive in mid June. The unofficial start occurred at the annual Fourth of July clambake. It took place on the shore of Frenchman’s Bay, close to the Lab buildings. Early in the morning, the student volunteers, under the professional eye of Nels Mitchell, dug a five by four foot pit, filled it with large rocks and wooden logs.
“A fire was lighted and allowed to burn for hours until the rocks were hot enough to cook the victuals. These included whole potatoes, corn on the cob, lobsters, clams and mussels, and protected by heavy burlap, the whole was covered over by beach sand and gravel. By early afternoon, the food was cooked to Nels’s satisfaction and the entire Lab entourage slowly assemble, bringing salads, breads, drinks, and huge appetites. This was the time when old friends greeted one another, children joyfully hugged last years playmates, and newcomers welcomed.”
The wives of the luminaries who summered by at the lab collected a cookbook, titled Kitchen Data, which includes a section on drinks:
“The secret of a good martini is not the ingredients alone but the ceremonial preparation. Take one gray earthen ware pitcher chilled in refrigerator, one wooden spoon (metal draws off heat), ice in pitcher. Add Gilbey’s gin and Noilly Pratt dry vermouth 3 to 1, stir for a few minutes, pour into glass with olive. Never add more ingredients than can be poured at once—a watered martini is not a dry martini. The host should be seated in a chair in the center of the party, and make the martinis in public view. Mixing in the kitchen or by flunkies, is ceremonially offensive.”
Gilbey’s and Noilly Pratt aside, Zubrod sees that good things happen when scientists gather formally or informally. Years later, reflecting on his career, Zubrod sets forth what could be dubbed a recipe for curing cancer:
“There is only a single lesson to be emphasized in this experience in designing curative regimens; namely, that the information needed to design a curative scheme for a particular cancer, given some highly active drugs, usually resides in a number of different individuals—both scientists and physicians.
“Somehow, the circumstances must permit those with the information to get together often, daily if possible, and to hammer out the combination of modalities that represents the best chance for cure. It does not matter whether this coming together is spontaneous, as in the case of choriocarcinoma, or more structured and engineered, as in ALL.
“What really matters is to have the right sorts of scientists and physicians… with innovative ideas, alert to every new advance in the relevant basic science, and with the motivation to work with many others toward a highly defined goal.”
In a nutshell, Zubrod’s approach to science is a relentless, jovial search for truth.
Zubrod is a young attending at Johns Hopkins University when his mentor, Phil Tumulty, is recruited to Saint Louis University.
On the surface, this may seem like a profound homecoming. Saint Louis University is not just a Catholic school, but a school run by the Society of Jesus.
Since Zubrod’s job at Hopkins is a dead end, there is nothing to lose:
“After six years at Hopkins, I did not perceive a clear cut academic future. The medical faculty had its share of scions of old Baltimore families, bringing an almost automatic progression from medical school and hospital training, to become part of the permanent staff. Rarely, an outsider with extraordinary intellectual gifts would break this barrier, but clearly, I did not fit this category.”
Embracing an opportunity to teach at a Catholic medical school, Zubrod discerns the will of the Holy Spirit.
Things turn out badly. “The St. Louis decision was prelude to a year of disaster, one that, as l reluctantly dredge from memory, fills me with horror at my stupidity,” Zubrod writes.
Zubrod and Tumulty, the chairman of the Department of Medicine, attempt to compel physicians to teach at the medical school as a condition of being able to admit patients to the hospital, Firmin Desloge.
A contingent of physicians objects, refusing to admit patients at Firmin Desloge, thereby depressing its revenues. Also, unbeknownst to Tumulty and Zubrod, the hospital is co-owned by the Jesuits and an order of nuns. The nuns, unnamed in this book, are the Sisters of St. Mary.
“The nuns were members of a nursing order originating in Germany, and while they were excellent nurses, many came from farming families and had had little opportunity to appreciate the hospital role of a university medical school,” Zubrod writes.
The hospital sacks Tumulty, and offers Zubrod his job. Of course, Zubrod says No, resigns in protest, and attributes this misfortune to the will of the Holy Spirit.
Soon thereafter, he is offered a job at NCI. “Approved at a salary of $15,000, (the same amount I received at St. Louis) I was to report 1 October 1954, as a commissioned officer in the United States Public Health Service,” Zubrod writes.
As an incoming clinical director, his humility edges over to doubt:
“Could I adapt to government service after 20 years of university life?; how would I, without experience in cancer research, provide leadership to scientists who had spent a lifetime studying cancer? I took comfort in Dr. Mider’s [C. Burroughs Mider, then NCI associate director in charge of research] conviction that the National Cancer Institute had mediocre clinical research and chemotherapy programs and that my leadership in both areas would provide what the Institute lacked.”
As soon as he gets established at NCI, Zubrod sends for Tom Frei, chief resident at St. Louis University. And, with the Holy Spirit or without, with the angels or without, they go on to make history.
Read Zubrod’s Stairway of Surprise here.
Otis Brawley is Bloomberg Distinguished Professor of Oncology and Epidemiology at Johns Hopkins University, and co-editor of the Cancer History Project.
Paul Goldberg is the editor & publisher of The Cancer Letter and co-editor of the Cancer History Project.