“The response of the first patient was as dramatic as that of the first mouse. … Within 48 hours after the initiation of therapy, a softening of the tumor masses was detected. It soon became obvious that this was not just wishful thinking. “—Alfred Gilman, Ph.D., “The Initial Clinical Trial of Nitrogen Mustard” (Amer. J. Surg. 1963;105:574–8).
The top-secret intravenous administration of 0.1 mg/kg “Compound X” to an “x-ray resistant patient in the terminal stages of lymphosarcoma” in early December 1942 marked the quiet birth of chemotherapy in America.
The clandestine, government-sanctioned treatment of an anonymous patient at Yale University, New Haven, Conn., signified the first therapeutic use of nitrogen mustard, a mysterious compound that had been under investigation since its devastating use as a chemical weapon during World War I.
Dr. Gilman, Dr. Louis S. Goodman, and their team watched in amazement as obstructive symptoms associated with tumor masses involving the patient's face, mediastinum, and submental regions were eased within 4 days, and cervical and axillary masses receded soon after.
Ultimately, the first patient's course proved to be less miraculous than it first seemed. The person's bone marrow “slowly recovered” from toxic effects of the new treatment, but—“a great disappointment”—the tumors returned concomitantly.
Thus began the wrenching ups and downs of patient response to mustard gas in quiet experimental protocols at Yale, the University of Chicago, and the then-Sloan-Kettering Institute of Memorial Hospital in New York.
Until 1946, government secrecy restrictions prevented publication of small case series, but the experiments continued, and on March 15, 1949, mechlorethamine (Mustargen) became the first chemical agent to receive Food and Drug Administration approval for the treatment of cancer, transforming an agent of death into one that held the promise of extended life and launching a revolution.
“It is actually quite remarkable that it has only been 60 years since the first chemotherapy approval, considering where the field has gone in that time,” said Dr. Richard Schilsky, professor of medicine at the University of Chicago and president of the American Society of Clinical Oncology. “We now have probably 100 or more chemotherapy drugs for the treatment of a wide range of different malignancies.”
The journey has been anything but smooth, with strong early opposition documented by Yale oncologists Vincent T. DeVita Jr. and Edward Chu in a recent article, “A History of Cancer Chemotherapy” (Cancer Res. 2008;68:8643–53). “Remissions turned out to be brief and incomplete, and this realization then created an air of pessimism that pervaded the subsequent literature of the 1950s,” they noted. Some academic physicians “became harsh critics of a national drug development program and the effort to prove that drugs could cure advanced cancer.”
By the 1960s, “the main issue of the day was whether cancer drugs caused more harm than good, and talk of curing cancer with drugs was not considered compatible with sanity. The prevailing attitude toward the use of chemotherapy can only be described as hostile,” wrote Dr. DeVita and Dr. Chu.
In spite of it all, chemotherapy emerged as a trusted modality in the treatment of cancer. The drug that started it all, Mustargen, became a key element in the revolutionary MOPP (Mustargen, Oncovin, procarbazine, and prednisone) combination chemotherapy regimen pioneered by Dr. DeVita for advanced Hodgkin's disease in the mid-1960s. It still is used today for stage III and IV Hodgkin's disease and other hematologic cancers, including polycythemia vera and mycoses fungoides, and bronchogenic carcinoma.
Initial observations regarding Mustargen were made during World War I, “when thousands were gassed,” leading to recognition of profound lymph and bone marrow suppression in exposed soldiers and speculation that the agent might have therapeutic utility in diseases characterized by lymphoid and myeloid proliferation, said Dr. DeVita, former director of the National Cancer Institute.
By early 1942, the government's Office of Scientific Research and Development entrusted Dr. Goodman and Dr. Gilman of Yale University to shepherd a highly classified investigation of the deadly agent. After preliminary work in mice, they persuaded Dr. Gustav E. Lindskog, then assistant professor of surgery at the university, to supervise the first human clinical trial.
Detractors objected to the empiric manner in which the early drugs were investigated; the research partnerships that evolved among government, academic, and contracted pharmaceutical companies; and perhaps, most important, the terrible burden of side effects exacted from patients not assured of a cure.
“These drugs were highly experimental and used as a last resort. At first, they didn't work very well and made people who were already sick much sicker,” said Dr. Franco Muggia, director of medical oncology at New York University and chairman and medical director of the Chemotherapy Foundation.