18 ONCOLOGY MARCH 1, 2009 • INTERNAL MEDICINE NEWS First FDA-Approved Chemo Agent Turns 60

BY BETSY BATES more chemotherapy drugs for the treatment of a wide range of dif- History of Chemotherapy: A Time Line “The response of the first patient was as dramatic as that of ferent malignancies.” the first mouse. ...Within 48 hours after the initiation of ther- The journey has been anything apy, a softening of the tumor masses was detected. It soon but smooth, with strong early op- First use of mustard gas on 1917 became obvious that this was not just wishful thinking.” position documented by Yale on- the battlefield, WWI. —Alfred Gilman, Ph.D., “The Initial Clinical Trial of Ni- cologists Vincent T. DeVita Jr. trogen Mustard” (Amer. J. Surg. 1963;105:574-8). and Edward Chu in a recent arti- cle, “A History of Cancer he top-secret intravenous administration of 0.1 Chemotherapy” (Cancer Res. Aitken 2nd Lt. T.L. United Kingdom Government 1942 Secret contract signed mg/kg “Compound X” to an “x-ray resistant pa- 2008;68:8643-53). “Remissions between U.S. Office of Ttient in the terminal stages of lymphosarcoma” turned out to be brief and in- Scientific Research and Yale in early December 1942 marked the quiet birth of complete, and this realization University to study chemical

chemotherapy in America. then created an air of pessimism Library and Archives Canada warfare agents; animal research begins. The clandestine, government-sanctioned treatment that pervaded the subsequent lit- Bari Incident: Mustard gas 1943 of an anonymous patient at Yale University, New erature of the 1950s,” they noted. released during bombing of December: First patient Haven, Conn., signified the first therapeutic use of ni- Some academic physicians “be- U.S. cargo ship in Italy. injected with “Compound X.” trogen mustard, a mysterious compound that had been came harsh critics of a national under investigation since its devastating use as a chem- drug development program and Mechlorethamine (first 1949 ical weapon during World War I. the effort to prove that drugs approved chemotherapeutic Dr. Gilman, Dr. Louis S. Goodman, and their team could cure advanced cancer.” drug) approved by FDA. watched in amazement as obstructive symptoms asso- By the 1960s, “the main issue of ciated with tumor masses involving the patient’s face, me- the day was whether cancer drugs diastinum, and submental regions were eased within 4 caused more harm than good, Methotrexate 1959 National Cancer Institute 1955 Cancer Chemotherapy days, and cervical and axillary masses receded soon after. and talk of curing cancer with (antifolate) approved National Service Center Ultimately, the first patient’s course proved to be less drugs was not considered com- by FDA. (drug development program miraculous than it first seemed. The person’s bone mar- patible with sanity. The prevailing at NCI) established. National Cancer Institute row “slowly recovered” from toxic effects of the new attitude toward the use of 5-Fluorouracil (antimetabolite) 1962 Vincristine (vinca alkaloid) treatment, but—“a great disappointment”—the tu- chemotherapy can only be de- approved by FDA. 1963 mors returned concomitantly. scribed as hostile,” wrote Dr. De- approved by FDA. POMP (methotrexate, Thus began the wrenching ups and downs of patient Vita and Dr. Chu. 1965 1967 MOPP (nitrogen mustard, vincristine, 6-mercaptopurine, vincristine, procarbazine, response to mustard gas in quiet experimental proto- In spite of it all, chemotherapy prednisone) used to treat prednisone) used in EWS cols at Yale, the University of Chicago, and the emerged as a trusted modality in N pediatric ALL. lymphoma. then–Sloan-Kettering Institute of Memorial Hospital in the treatment of cancer. The MOMP (nitrogen mustard,

New York. drug that started it all, Mustar- 1970s Adjuvant therapy era. EDICAL

vincristine, methotrexate, M Until 1946, government secrecy restrictions prevent- gen, became a key element in prednisone) used in Cisplatin (first platinum Hodgkin’s disease. 1978 ed publication of small case series, but the experiments the revolutionary MOPP (Mus- derivative) approved. LOBAL continued, and on March 15, 1949, mechlorethamine targen, Oncovin, procarbazine, G Paclitaxel approved. 1992 (Mustargen) became the first chemical agent to receive and prednisone) combination 1996 Irinotecan approved. LSEVIER

Food and Drug Administration approval for the treat- chemotherapy regimen pio- E ment of cancer, transforming an agent of death into one neered by Dr. DeVita for ad- that held the promise of extended life and launching a vanced Hodgkin’s disease in the mid-1960s. It still is used the agent might have therapeutic utility in diseases char- revolution. today for stage III and IV Hodgkin’s disease and other acterized by lymphoid and myeloid proliferation, said Dr. “It is actually quite remarkable that it has only been hematologic cancers, including polycythemia vera and DeVita, former director of the National Cancer Institute. 60 years since the first chemotherapy approval, con- mycoses fungoides, and bronchogenic carcinoma. By early 1942, the government’s Office of Scientific sidering where the field has gone in that time,” said Dr. Initial observations regarding Mustargen were made Research and Development entrusted Dr. Goodman Richard Schilsky, professor of medicine at the Univer- during World War I, “when thousands were gassed,” and Dr. Gilman of Yale University to shepherd a high- sity of Chicago and president of the American Society leading to recognition of profound lymph and bone mar- ly classified investigation of the deadly agent. After pre- of Clinical Oncology. “We now have probably 100 or row suppression in exposed soldiers and speculation that liminary work in mice, they persuaded Dr. Gustav E. Lindskog, then assistant professor of surgery at the uni- versity, to supervise the first human clinical trial. Future of Cancer Treatment Includes Chemotherapy Detractors objected to the empiric manner in which the early drugs were investigated; the research part- eople have been trying to curing the solid tumors that af- tion regimens that also may in- nerships that evolved among government, academic, Pwrite the epitaph for flict most patients with cancer. clude molecular-targeted agents. and contracted pharmaceutical companies; and per- chemotherapy virtually since ni- “Methotrexate and 5-fluo- “As we get into targeted thera- haps, most important, the terrible burden of side effects trogen mustard was approved in rouracil are among the most tar- py, there are some problems with exacted from patients not assured of a cure. 1949. But the naysayers were geted drugs we’ve ever had,” Dr. that as well,” he added. “These drugs were highly experimental and used as shortsighted then, and still are Schilsky said. “They’re more Dr. DeVita echoed the notion a last resort. At first, they didn’t work very well and today, a number of leading on- than 50 years old and have not that “targeted therapy is made people who were already sick much sicker,” said cologists maintain. been replaced.” chemotherapy.” Dr. Franco Muggia, director of medical oncology at For all the talk of “targeted” Although agents designed to “We always hoped, over time, New York University and chairman and medical direc- therapy taking center stage in target characteristics unique to tu- that chemotherapy would be- tor of the Chemotherapy Foundation. cancer therapy, “chemotherapy is mor cells may be the hope of the come more specific and it has,” But early believers pressed on, confident that the reg- likely to be an important part of future, to date they have matched he said. “Nitrogen mustard was imens could be fine-tuned, the toxicities tamed. In time, cancer treatment for some time chemotherapy’s success only in a the first use of systemic therapy dramatic advances were made in dosages and treatment to come,” Dr. Schilsky said. few rare tumor types, he added. based on the premise that treat- regimens, in combining chemotherapeutic agents and The belief that chemotherapy Empiric studies of early ment failure was due to circulat- in using them in various ways with surgery, radiation, is too toxic, and therefore should chemotherapeutic drugs may ing cancer cells. All subsequent and biologic therapies. A better biologic understand- be replaced by “targeted therapy,” look “pretty unsophisticated” to- systemic therapy, including bio- ing of cancer led to more precise targeting of negates several truths; one, that day, but the signals that resulted logics, is based on that premise.” chemotherapy. And progress was made in treating the chemotherapy isn’t “targeted,” were strong, Dr. Muggia agreed. Progress in cancer therapy, side effects that once seemed to be chemotherapy’s and two, that molecular-targeted “There’s no one way,” he said, then, is likely to build on lessons death knell, a point illustrated by Dr. Schilsky. therapies such as biologics and predicting that chemotherapy will of the past and encounter hurdles The experts consulted for this article have conduct- immunotherapy are capable of long play a key role in combina- not foreseen, Dr. DeVita said. ed research for pharmaceutical companies that manu- facture various forms of chemotherapy. ■