Frei E III, Holland JF, Schneiderman MA, et al. A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood. 1958;13(12):1126-1148.

This article presents one of the first cooperative multicenter comparative trials in modern clinical oncology. The authors introduce the innovative concept of combination chemotherapy consisting of 2 antimetabolites and a corticosteroid. Two schedules were prospectively compared. Randomizing patients was also novel, and the ethical issues are discussed. In those days, acute myeloid leukemia and acute lymphoblastic leukemia (ALL) could not be distinguished, and the same treatment was applied to both. Remarkably, survival was better for patients responding to chemotherapy. Many of these authors continued their seminal contributions to developmental cancer therapy, and one (Donald Pinkel) would pioneer the successful “total therapy” for pediatric ALL.