The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

As Freireich, Frei, and Zubrod studied the growing list of anti-leukemia drugs, the notion of combining drugs emerged with growing clarity: toxicities notwithstanding, annihilating leukemia might involve using a combination of two or more drugs. The first protocol was launched to test different doses of Farber’s methotrexate combined with Burchenal’s 6-MP, the two most active antileukemia drugs. Three hospitals agreed to join: the NCI, Roswell Park, and the Children’s Hospital in Buffalo, New York. The aims of the trial were kept intentionally simple. One group would be treated with intensive methotrexate dosing, while the other group would be treated with milder and less intensive dosing. Eighty-four patients enrolled. On arrival day, parents of the children were handed white envelopes with the randomized assignment sealed inside. Despite the multiple centers and the many egos involved, the trial ran surprisingly smoothly. Toxicities multiplied; the two-drug regimen was barely tolerable. But the intensive group fared better, with longer and more durable responses. The regimen, though, was far from a cure: even the intensively treated children soon relapsed and died by the end of one year.