Revolutionizing the Treatment of Childhood Leukemia
Frei and Freireich revolutionized the treatment of childhood leukemia. The 1955 trial constituted the first ever quantitative, prospective, experimental design for cancer treatment, demonstrating that complete remission after treatment with 6-MP ormethotrexate most reliably prognosticated survival. Achieving complete remission quickly became the initial goal. Patients were treated even after that point because of the recognition that it was not possible to be certain that every leukemia cell had been killed. In fact, almost surely they had not.
To address the problem of patient relapse and drug resistance, Frei and Freireich two years later launched the modern era of combination chemotherapy in a clinical trial treating patients by one drug first—methotrexate or 6- MP—and then by the other. For achieving complete remission, the combined use proved more effective than either drug used alone. That same year, the pair overcame considerable opposition within NCI and demonstrated the ability of blood platelet transfusions to stop hemorrhaging in leukemia patients.
In 1959, their clinical trial using prednisone to achieve complete remission followed by 6-MP established the principle of continuing adjuvant chemotherapy even in the presence of complete remission. They had an especially fertile year in 1961, proving that full doses of combined cyclophosphamide (CPA), 6-MP, and methotrexate after complete remission with prednisone were far superior to half doses of each in sustaining complete remission. They proved that the best results depend on fine-tuning delivery schedules, and they achieved their best results with complete remission induced by vincristine and prednisone followed up by adjuvant treatment with 6-MP and methotrexate.
In 1962, Freireich suggested on a creative hunch a four-drug regimen that soon acquired the acronym VAMP—vincristine, amethopterin (methotrexate), 6-MP, and prednisone-each administered in a full dose. Freireich guessed that since each drug had a different method of killing leukemia cells, maximum doses could be administered without increasing toxicity.
“At first I opposed it,” confessed Gerald Bodey, a specialist in infectious disease who worked with Frei and Freireich. “Giving these kids four drugs all at once! As a Christian, I thought it was immoral because if they relapsed we would have no fallback. I thought Freireich was crazy.” The results stunned Bodey. “We had sixteen patients, and eleven were cured. It was astonishing. I kept track of one of the children for decades until she died of breast cancer.” Frei was awed, “To be able to do this with a lovely child . . . whom you think of almost as your own, is truly an extraordinary experience. . . . I had the evidence that you could succeed.”
An excerpt from "Making Cancer History: Disease and Discovery at The University of Texas M. D. Anderson Cancer Center", by James S. Olson, Ph.D.
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Johns Hopkins University Press