Yale 1942: Goodman, Gilman and the First Nitrogen Mustard Trial, Patient J.D. | Day 115

"J.D." and the Secret Dose: Goodman, Gilman and the First Chemotherapy Trial at Yale, 1942

A drug nobody was seeking for cancer

At the start of 1942, two pharmacologists at Yale, Louis Goodman and Alfred Gilman, were carrying out classified work for the US Office of Scientific Research and Development (OSRD). The subject was the effect of sulfur and nitrogen "mustard" compounds on the body. These substances had been known as chemical agents since the First World War; the real question was to understand how a chemical agent harms the body and to look for countermeasures. There were also observations from mustard gas exposure in the First World War that blood cells and lymphoid tissue were affected; those wait in the plan as a separate post, and we do not enter them today.

Goodman and Gilman carried out their work in mice and rabbits. According to Yale's accounts, lymphoma in mice shrank with nitrogen mustard and even showed a "dramatic regression". One mouse that is described gives a small sketch of the pattern: a large tumour first regressed with treatment, then grew back; the second treatment was less effective, the third not at all; even so, treatment had markedly prolonged the mouse's life. The patient story below will resemble the human counterpart of that sketch. The dates of the experiments are not given in the accounts.

To move from laboratory to patient a surgeon was needed. Gustaf Lindskog, an assistant professor of surgery at Yale, recommended a lymphoma patient whose treatment options had run out to the pair. Lindskog later became chair of surgery at Yale; in this post we mention him only as the recommending physician.

A patient's ninety-eight days

On 31 August it was noted that J.D. could sleep more comfortably, eat and move. By 6 September he had improved markedly; but on the same day his white blood cell count had begun to fall. On 27 September all the nodes in his neck and armpits are recorded as gone. Within about a month the cancer could no longer be detected on examination. This is the scene cited as one of the first recorded trials of intravenous chemotherapy: a drug was given through a vein and acted at once on lymph nodes in many parts of the body. But the story does not end there.

In mid-October the lymphosarcoma returned. According to Yale's account the remaining cells had become resistant to nitrogen mustard. The second course had only a short effect; the six-day third course that began on 6 November had little. Bone marrow suppression, bleeding and breathing difficulty developed. J.D. lost his life on 1 December 1942, on the ninety-sixth day of his hospital stay.

Why a lymphoma? The sources do not discuss it; my interpretation is this: nodes in the neck and armpits can be followed by hand and eye, so it was possible to watch a drug's effect day by day. The shrinking and then regrowth of the same nodes was the most concrete sign that the drug was truly doing something in the body. In other words, J.D.'s lymphoma was both a disease and a measuring instrument.

That had a cost too: what could be measured was only the visible nodes. For disease in the bone marrow or elsewhere, invisible on examination, they could not ask the same question. The problem of the "unseen cell" that we met on Day 114 reminded us of itself even in the first response to the first systemic drug.

The year secrecy lifted, and a late correction

According to Yale's account, after J.D. 67 patients across the country were treated in this way, seven of them at Yale. Goodman and Gilman left Yale in 1943. In 1946, when military secrecy lifted, the results were published in two places: the patient series by Goodman and colleagues in JAMA and the broad review by Gilman and Philips in Science. In 1963 an article titled "the initial clinical trial of nitrogen mustard" appeared in the American Journal of Surgery; it is attributed to Gilman.

But J.D.'s identity and details were relayed wrongly for a long time. Two Yale physicians, John Fenn and Robert Udelsman, searched for the patient's records for about two years; the work was hard because the full name and record number were not known, and only when an archivist corrected record numbers did they narrow it to one patient. Their results were published in 2011 in the Journal of the American College of Surgeons: "first use of intravenous chemotherapy cancer treatment: rectifying the record". Saying "first" in the title is a claim; here I relay it as "the first recorded trial of intravenous chemotherapy".

Official approval came later: mechlorethamine is cited as the first chemical agent approved for cancer, on 15 March 1949. The timeline of this post stops at 1946; 1949 is the subject of a separate post, and when we get there we will check separately the licensing history of the same drug.

The lesson this story leaves today has two layers. First, the 1942 trial showed that a drug able to go beyond the limits of local methods was possible. Second, it showed that the first response of that method was not lasting and that resistance came at once; the later history of chemotherapy was written largely between these two observations.

The first use of nitrogen mustard in Turkey

I could not reach a verified source on when and how nitrogen mustard reached Turkey; so I draw no link and give no date. The general inference is this: the results published in 1946 entered circulation in the international literature, and how long it took them to reach countries and hospitals is a separate research subject. It will be taken up, with its sources, in the part of the series devoted to Turkey.

This post is Day 115 of the "365 Days of Cancer History" series and recounts the 1942 nitrogen mustard trial at Yale as a historical event. It is a historical-popular account, not advice on diagnosis or treatment. For your own health, consult your physician. Sources have been verified; details resting only on secondary sources are marked in the fact-check notes.