A New Frontier
I look on each patient as not only a project to do the best for that patient, but to learn the most from that patient for future patients.
- Raymond Alexanian, MD Anderson Oral History, May 15, 2014
Cancer is expensive. Really expensive. Consider this: while grassroots fundraisers, philanthropy, and private donations raise a lot of money for medical research, total amounts pale when compared to federal spending. That’s why it’s important to recall the first burst of significant taxpayer-support for cancer (and myeloma), which is very much a legacy of the Cold War.
As we have seen, superpower tensions caused by the Soviet Union’s 1957 launching of the first space satellite, Sputnik, led to a years-long delay in American access to the cancer drug melphalan, a Soviet discovery. Moreover, this widespread sense of urgency created a nationwide angst making cancer research, in a roundabout way, a favored beneficiary in the response to it.
Historians cite John F. Kennedy’s New Frontier speech, given to accept the 1960 Democratic presidential nomination, as the beginning of the space race. Many thought it was “won” when Neil Armstrong set foot on the moon in 1969. The speech, practically dictated by fear of a Soviet domination of science, articulated how scientific inquiry and achievement had national purpose; rapid scientific progress would add soft power muscle to the nation’s superpower arsenal.
Disease, like space, was a “frontier of unknown opportunities and perils – a frontier of unfulfilled hopes and threats,” Kennedy emphasized, “the times demand invention, innovation, imagination, decision.” Every citizen should have a fair opportunity to attain the promise of the New Frontier, he declared.
Shortly after Kennedy took office, unprecedent congressional support granted unprecedented funds to transform some hospitals into research and treatment clinics. Throughout the nation, medical facilities added equipment and, more consequentially, staff.
If we pledged to land on the moon by the end of the decade, why couldn’t we do something like cure cancer? Or so the overly optimistic reasoning went.
The concept of “bench-to-bedside” was born. Speed up and refine capabilities, constantly inform researchers about clinical efficacy and vice versa. Indeed, it has become, ideally, a circular, never-ending cycle of “bench-to-bedside-to-bench” and so on.
The National Cancer Institute (NCI) planned to transform selected regional clinics into robust research and treatment facilities, building new, state-of-the-art facilities attracting some of the best young minds into cancer research. New funding was a windfall for respected teaching hospitals like the Mayo Clinic, Dana-Farber in Boston, Memorial Sloan Kettering in New York, and in fast-growing Sun Belt cities like Houston.
MD Anderson Hospital helped transform a sleepy, sweltering, humid city into the sixth most populous in the United States. Numerous new research and clinician positions gave attention to rare diseases that had been neglected either because of a lack of patients or scientific knowledge.
But first, leadership had to be recruited if it was to make the transformation from a regional hospital to a world-leading cancer center.
One of the most consequential ideas in cancer coming out of NCI in the mid-1950s had nothing to do with labs, experiments, or treatments.
A brilliant cancer researcher, Emil Freireich, conceived a system of institutional cooperation to conduct clinical trials for diseases with small numbers of patients. It was the only way they could get reliable data.
Today, American-based cooperative groups—ECOG, SWOG, the Alliance—run and coordinate clinical trials for virtually every cancer type. New Frontier-related funding created reliable networks of clinics and disease specialists around the country who could work together with identical protocols to create larger patient pools, testing new ideas systematically.
Freireich was recruited in the early 1960s by his former NCI colleague, Tom Frei, another cancer pioneer, to move to MD Anderson – a salary increase from $6,000 to $25,000 surely helped – to co-lead a new developmental therapeutics department. It would be separate from hematology, but time would demonstrate much overlap.
Together Freireich, who was soon to be known as “the father of modern leukemia therapy,” and Frei would change the world for patients with hematological malignancies. Myeloma wasn’t high on their to do list; it would never be a priority. And Freireich didn’t yet know one of his future hires would inspire a generation of physicians to make myeloma one of theirs, changing the field forever.
Bergsagel got an offer to go back to his home country in 1964. He got an offer from James Till and Ernest McCulloch at Princess Margaret Hospital in Toronto, Canada.
Till and McCulloch are considered to be among most consequential cancer researchers. They made a fortunate mistake with lab mice which identified a central issue in myeloma: stem cells in blood. We’ll learn more about them in the future.
Bergsagel worked in leadership roles with Till and McCullogh to help transform Princess Margaret from a twelve-bed hospital into the leading medical institution in the nation.
And while Bergsagel never got to take advantage of much of the new NCI/New Frontier money, he would leave another great in myeloma; he hired a man who—although he would later admit knowing little about myeloma—turned out to be the right person at the right time to make notable contributions to myeloma treatment.
Raymond Alexanian joined MD Anderson’s hematology faculty in 1964. Houston would be his home for the rest of his life.
A growing Texas metropolis was as alien a place imaginable for a lower working-class son of a Bronx grocer who went on to earn an Oxford PhD in hematology in the previous sixteen of this thirty-two-years. Stops along the way went from Dartmouth, the Harvard Medical School, an army stint in Japan as an “obligated volunteer,” Christie Hospital in Manchester, England – the first hospital ever devoted exclusively to cancer care, to the University of Washington at Seattle.
His reserved, intense discipline was likely inherited from his grandfather, an Armenian surgeon in the Ottoman (Turkish) Empire during World War I. His service saved the family from falling victim to a genocide claiming more than a million Armenian lives. After the war, they emigrated to the U.S., first to Philadelphia.
Alexanian’s father became a grocer in the Bronx. Contracting polio around the age of three left a young Raymond with one leg shorter than the other, requiring a lift in one shoe and causing him to walk with a noticeable limp for the remainder of his life. His inability to move quickly was balanced by a thorough studiousness that translated into inordinate patience in his lab work and endeared him to his patients.
Alexanian’s reputation in hematology was built on his research in erythropoietin (EPO), an essential kidney-produced hormone essential to creating red blood cells. EPO counters the effects of anemia, caused by too few blood cells due to blood loss or disease. Production increased in high elevations, where oxygen is thinner and red blood cells must work harder to keep the circulatory system functioning. But it could not be measured.
Alexanian focused on EPO’s source, the kidneys. His solution, twenty-four-hour urine collection, has since become a standard diagnostic procedure for many diseases with kidney involvement. Myeloma patients everywhere could tell stories about collecting urine over a twenty-four-hour period so that labs could condense it to measure EPO.
In myeloma, kidney function is often impeded by large calcium deposits from disintegrating bone. Alexanian’s understanding of endocrinology, the science of hormones that basically regulate our essential biological functions like sleep or regulating the body’s temperature, proved to be essential in some aspects of cancer and its treatment.
With the discovery, Alexanian became a sought-after speaker in clinics throughout the nation. Few medical outsiders understand the real value of these types of opportunities. At a time when telephones and taking notes by hand were cutting edge, speaking engagements were also vital to continuing education. Medical professionals from different places could discuss ideas together, eye-to-eye rather than weeks-long correspondence and calls.
Gaining medical expertise was, Alexanian would learn, as much a craft as an academic pursuit. While discussing the dearth of options available to myeloma patients with Frei, they went down the list. Melphalan.
Alexanian mentioned a steroid called prednisone that had been successful in reducing high calcium levels. Fluoride was showing promise in teeth, teeth were bones, maybe it would help in myeloma. And there was EPO. The result of the conversation was one of the most crucial in the history of myeloma.
Frei suggested a “cocktail” of drugs, why not combine them, to see if it had any effect? Prednisone seemed to have the most promise. Steroids target the adrenal glands, which rest on top of kidneys, to produce cortisol, a hormone regulating proteins, sugars, fats, carbohydrates, blood pressure, and inflammation throughout the body.
When added to melphalan, prednisone acted as a “turbo-booster” to intensify the effect of chemotherapies by, stimulating the adrenal glands to produce cortisol. But it also had it side effects, like all steroids. Insomnia, bloating, and difficulty in controlling irritability were just a few. He prescribed prednisone in short spurts to lessen the side effects.
The results of melphalan-prednisone were so good, they became a standard myeloma therapy for much of the next two-plus decades. The combination raised average survival rates to as much as three years. More significantly, it previewed a new concept in cancer therapy: drug combinations. Over time, the impact of future combination therapies would transform myeloma treatment.
After returning to Canada, Bergsagel continued to mentor Alexanian over long distance. Their successful collaboration would be integral in developing a new approach to treat myeloma, one that would be propelled in myeloma at MD Anderson in the coming years by a young, ambitious medical school graduate who would leave Germany forever to become one of Freireich’s disciples and Alexanian’s colleagues.
When Daniel Bergsagel arrived at MD Anderson, the hospital didn’t even accept appointments for myeloma patients. Patients generally died within six months and there was nothing to do.
Within a decade, people and events at MD Anderson would transform myeloma research. But it did little to impact overall survival statistics, unlike many other cancers of the institution’s growing portfolio. That would change in the coming decades. Houston would become a destination for myeloma patients throughout the world.
While things were happening in Houston, Robert Kyle was just as active in other areas in Rochester, Minnesota. We’ll catch up with him in the next article.
Photo: Detail, Vincent Van Gogh, Wheatfield with a Reaper (1889), Van Gogh Museum, Amsterdam, Netherlands
Today SWOG, ECOG, and Alliance are definitely NOT geographically based