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Surgeons-turned-detectives explore the dawn of chemotherapy

Medicine@Yale, 2011 - March April

Thanks to the unearthing of long-lost medical records by two dogged surgeons, the full story of the first use of intravenous chemotherapy for cancer, which occurred at Yale in the early 1940s, can now be told.

The general outlines of this event—that a lymphoma patient, known only as “J.D.” in the medical literature, received the first known chemotherapy at New Haven Hospital (now Yale-New Haven Hospital) in 1942—have been recounted by historians based on the recollections of those involved in the case, but the specifics have until now remained a mystery.

Two years ago, Clinical Professor of Surgery John E. Fenn, M.D. and Robert Udelsman, M.D., M.B.A., chair and William H. Carmalt Professor of Surgery, became fascinated by J.D.’s case and determined to try to locate his medical records. The problem was that they had no name, date of birth, medical record number, or precise dates of treatment—only the patient’s initials.

For months the two pursued records from that era, including pathology reports, of every “J.D.” they could find. Michael Kashgarian, M.D., professor emeritus and senior research scientist in the Department of Pathology, whom they’d enlisted to help, finally found a report that looked promising, but the medical record number contained errors. Thanks to the help of a persistent archivist, they eventually narrowed the possibilities down to one patient. In a moment of triumph, Fenn sent Udelsman a one-word e-mail: FOUND!

The records revealed that an immigrant from Poland first came to New Haven Hospital in 1941 for treatment of massive tumors in and around his neck that had diminished his ability to eat, sleep, breathe, and turn his head. Radiation treatments were quite effective at first, but by August of the following year the tumors had recurred and had developed resistance to treatment with X-rays. As no other therapeutic options for cancer had yet been developed, doctors had nowhere else to turn.

At about the same time, under the auspices of the War Department’s Office of Scientific Research and Development, formed by President Franklin D. Roosevelt, School of Medicine faculty members were conducting highly classified research projects to support the Allies’ effort in World War II. Pharmacologists Louis S. Goodman, M.D., and Alfred Gilman, Ph.D., were searching for antidotes to mustard gas, the chemical warfare agent that had been used to such devastating effect in World War I.

In studies of nitrogen mustard, a relative of the poison gas, Goodman and Gilman observed that lymph cells in animals were particularly sensitive to the compound’s toxicity, which led them to wonder whether it would also kill lymphoma cells. Indeed it did: when nitrogen mustard was administered intravenously to mice with lymphoma, their tumors shrank rapidly and soon disappeared, an unexpected and unprecedented result. However, mirroring J.D.’s response to radiation treatment, the tumors recurred, and subsequent treatments with nitrogen mustard were less and less effective.

Nonetheless, the tumor regression in the mice had been dramatic and had significantly increased their survival time. Goodman and Gilman were eager to test nitrogen mustard clinically, and they approached Gustav E. Lindskog, M.D., then an assistant professor (he would ultimately go on to chair the Department of Surgery), about attempting an experimental nitrogen mustard treatment of J.D.’s terminal cancer.

On August 25, 1942, J.D., recognizing that he had no other alternatives, consented to the treatment and became the first patient to receive intravenous chemotherapy for cancer. By the end of September his tumors had completely regressed and no cancer cells were detectable in a biopsy of his lymph nodes. Unfortunately the tumor returned by mid-October, and just as Goodman and Gilman had observed in animals, the newly emerged tumor displayed increasing resistance to nitrogen mustard, which was also found to be toxic to white blood cells. On December 1, 1942, after 96 days in the hospital, J.D. died.

Fenn and Udelsman say that J.D.’s case was immensely important because it revealed three aspects of chemotherapy—tumor regression, tumor resistance, and toxic side-effects—that shaped the development of better oncology drugs thereafter. Nearly 70 years later, the pair has published a paper in the March issue of the Journal of the American College of Surgeons that tells the story of the sleuthing that uncovered J.D.’s medical record, and also clarifies and corrects many of the specifics of his case.

J.D.’s hospital admission record, written up by a Yale medical student, fills in the detail that had until now been missing by describing the patient’s management, the events that led to the use of nitrogen mustard for treatment, the patient’s social and personal history, and how the decision to attempt chemotherapy emerged. The student’s drawings in the medical record are “beautiful,” Udelsman says. “This was the birth of medical oncology.”