A History of Cancer Chemotherapy
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`Vincent T. DeVita, Jr. and Edward Chu
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`A History of Cancer Chemotherapy
`
`Vincent T. DeVita, Jr. and Edward Chu
`
`Yale Cancer Center, Yale University School of Medicine, New Haven Connecticut
`
`Abstract
`The use of chemotherapy to treat cancer began at the start of
`the 20th century with attempts to narrow the universe of
`chemicals that might affect the disease by developing methods
`to screen chemicals using transplantable tumors in rodents.
`It was, however, four World War II–related programs, and the
`effects of drugs that evolved from them, that provided the
`impetus to establish in 1955 the national drug development
`effort known as the Cancer Chemotherapy National Service
`Center. The ability of combination chemotherapy to cure acute
`childhood leukemia and advanced Hodgkin’s disease in the
`1960s and early 1970s overcame the prevailing pessimism about
`the ability of drugs to cure advanced cancers, facilitated the
`study of adjuvant chemotherapy, and helped foster the national
`cancer program. Today, chemotherapy has changed as impor-
`tant molecular abnormalities are being used to screen for
`potential new drugs as well as for targeted treatments. [Cancer
`Res 2008;68(21):8643–53]
`
`Introduction
`In the early 1900s, the famous German chemist Paul Ehrlich set
`about developing drugs to treat infectious diseases. He was the one
`who coined the term ‘‘chemotherapy’’ and defined it as the use of
`chemicals to treat disease. He was also the first person to document
`the effectiveness of animal models to screen a series of chemicals
`for their potential activity against diseases, an accomplishment that
`had major ramifications for cancer drug development. In 1908, his
`use of the rabbit model for syphilis led to the development of
`arsenicals to treat this disease. Ehrlich was also interested in drugs
`to treat cancer,
`including aniline dyes and the first primitive
`alkylating agents, but apparently was not optimistic about the
`chance for success. The laboratory where this work was done had a
`sign over the door that read, ‘‘Give up all hope oh ye who enter.’’
`Surgery and radiotherapy dominated the field of cancer therapy
`into the 1960s until it became clear that cure rates after ever more
`radical local treatments had plateaued at about 33% due to the
`presence of heretofore-unappreciated micrometastases and new
`data showed that combination chemotherapy could cure patients
`with various advanced cancers. The latter observation opened up
`the opportunity to apply drugs in conjunction with surgery and/or
`radiation treatments to deal with the issue of micrometastases,
`initially in breast cancer patients, and the field of adjuvant
`chemotherapy was born. Combined modality treatment,
`the
`tailoring of each of the three modalities so their antitumor effect
`could be maximized with minimal toxicity to normal tissues, then
`became standard clinical practice (1–4).
`
`Requests for reprints: Vincent T. DeVita, Jr. or Edward Chu, Yale Cancer Center,
`Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. Phone:
`203-787-1010; Fax: 203-785-2875; E-mail: vincent.devita@yale.edu or chueyale@
`yahoo.com.
`I2008 American Association for Cancer Research.
`doi:10.1158/0008-5472.CAN-07-6611
`
`AACR Centennial Series
`
`The Early Period of Cancer Drug Development
`A selected history and timeline of events related to the
`development of cancer chemotherapy is shown in Fig. 1. The first
`four decades of the 20th century were primarily devoted to model
`development. The major limitations of drug discovery were two-
`fold: first, the development of models that could effectively be used
`to reduce the vast repertoire of chemicals to those few that might
`have activity against cancer in humans, and second, the access to
`clinical facilities to test such agents.
`A major breakthrough in model development occurred in the early
`1910s when George Clowes of Roswell Park Memorial Institute (RPMI)
`in Buffalo, New York, Roswell Park Memorial Institute developed the
`first transplantable tumor systems in rodents. This advance allowed
`the standardization of model systems and the testing of larger
`numbers of chemicals. Significant efforts were subsequently focused
`on identifying the ideal model system for cancer drug testing, which
`then became a major thrust of research for the next several decades
`(5–11). The early model systems that were developed included
`Sarcoma 37 (S37), Sarcoma 180 (S180), Walker 256, and Ehrlich’s
`ascites tumor, all carcinogen-induced tumors in mice.
`It was Murray Shear, at the Office of Cancer Investigations of the
`USPHS, a program that was later combined in 1937 with the NIH
`Laboratory of Pharmacology to become the National Cancer Institute
`(NCI), who in 1935 set up the most organized program that would
`became a model for cancer drug screening (7). Shear’s program was
`the first to test a broad array of compounds, including natural
`products, and had both interinstitutional and international collab-
`orations. He ultimately screened over 3,000 compounds using the
`murine S37 as his model system. However, because only two drugs
`ever made it to clinical trials and were eventually dropped because of
`unacceptable toxicity, the program was dissolved in 1953 just as
`discussions began about establishing an organized national effort in
`drug screening. This failure was in part due to the antipathy toward
`the testing of drugs to treat cancer but also to a lack of information
`and experience on how to test potentially toxic chemicals in humans.
`The most excitement
`in this era was generated by the
`introduction of hormonal therapy when, in 1939, Charles Huggins,
`based on an early observation on the effect of estrogens on breast
`cancer made by Beatson in 1896 (12), treated men with prostate
`cancer with hormones and was able to show responses by decreases
`in acid phosphatase levels (13). Although this exciting piece of work
`was an important addition to the systemic treatment of cancer and
`earned Huggins a Nobel Prize, it was not considered to be related to
`the issue of whether chemicals could ever control cancer.
`
`World War II and the Immediate Post-War Period
`Although gases were not used on the battlefield in World War II
`(WWII), a great deal of research was done on vesicant war gases
`(5, 8). The experience in WWI and the effects of an accidental spill
`of sulfur mustards on troops from a bombed ship in Bari Harbor,
`Italy,
`in WWII (14, 15) led to the observation that both bone
`marrow and lymph nodes were markedly depleted in those men
`exposed to the mustard gas. Consequently, Milton Winternitz at
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`Yale, who had worked on sulfur mustards in WWI, obtained a
`contract to study the chemistry of the mustard compounds from
`the U.S. Office of Scientific Research and Development and asked
`two prominent Yale pharmacologists, Alfred Gilman and Louis
`Goodman, to examine the potential therapeutic effects of these
`chemicals. Goodman and Gilman carried out experiments in mice
`bearing a transplanted lymphoid tumor with one compound,
`nitrogen mustard. When they observed marked regressions, they
`convinced their colleague Gustaf Lindskog, a thoracic surgeon, to
`administer nitrogen mustard to a patient with non–Hodgkin’s
`lymphoma and severe airway obstruction. Marked regression was
`observed in this and other lymphoma patients. The initial study
`was done in 1943 but because of the secrecy associated with the
`war gas program, the results were not published until 1946 (16–18).
`The 1943 results set off a burst of support for the synthesis and
`testing of several related alkylating compounds,
`including oral
`derivatives such as chlorambucil and ultimately cyclophosphamide.
`The use of nitrogen mustard for lymphomas spread rapidly
`throughout the United States after the publication of the Lindskog
`article in 1946. If one reads the literature of the time, there was a real
`sense of excitement that perhaps drugs could cure patients with
`cancer (19). Unfortunately, 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. A cadre of
`academic physicians,
`led by the famous hematologist William
`Dameshek, who having seen apparent success turn to failure could
`never again be persuaded that cancer was curable by drugs (20),
`became harsh critics of a national drug development program and
`the effort to prove that drugs could cure advanced cancers.
`Nutritional research before and during WWII had identified a
`factor present in green leafy vegetables that was important for bone
`marrow function. This factor turned out to be folic acid, which was
`first synthesized in 1937. It was later shown that folate deficiency
`could produce a bone marrow picture reminiscent of the effects of
`nitrogen mustard. Farber, Heinle, and Welch tested folic acid in
`leukemia and they came to the conclusion that it actually acce-
`
`lerated leukemia cell growth (21). Although this observation was
`later proved to be spurious, Farber collaborated with Harriet Kilte
`of Lederle Laboratories to develop a series of folic acid analogues,
`which were in fact folate antagonists, and these compounds included
`aminopterin and amethopterin, now better known as methotrexate.
`Farber subsequently tested these antifolate compounds in children
`with leukemia and, in 1948, showed unquestionable remissions (22).
`Another WWII-related program was the large-scale screening of
`fermentation products by the pharmaceutical industry to isolate
`and produce antibiotics to treat wound infections, based on the
`observations on penicillin. Antitumor effects were examined for
`some agents as well. Penicillin was even initially thought to have
`antitumor properties that were never confirmed. The antibiotic,
`actinomycin D, came from this program. It had significant antitumor
`properties and enjoyed considerable use in pediatric tumors in the
`1950s and 1960s (23). This drug established the initial interest in the
`search for more active antitumor antibiotics, and this effort yielded
`a series of active antitumor antibiotics in common use today.
`Finally, a fourth WWII government effort conducted by the Com-
`mittee on Medical Research of the Office of Scientific Research and
`Development, the antimalarial program, served as an organizational
`model and a source of talent. The success in the search for synthesis
`and production of effective antimalarial compounds in WWII showed
`that a nationally organized, well-supported effort, tightly focused on a
`disease, could yield positive results. Several of the individuals who
`later organized the national effort of the NCI had experience with this
`program in WWII and believed the same kind of effort would yield
`positive results developing drugs against cancer (14).
`The early activity of nitrogen mustard and methotrexate also
`provided a great stimulus for the synthesis of other drugs in
`addition to alkylating agents and antifols. In 1948, the same year
`that Farber showed the antifolate activity of methotrexate in
`childhood leukemia, Hitchings and Elion isolated a substance that
`inhibited adenine metabolism. By 1951, they had developed two
`drugs that would later play an important role in the treatment of
`acute leukemia: 6-thioquanine and 6-mercaptopurine (24, 25).
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`History of Cancer Chemotherapy
`
`activity against a range of solid tumors and, to this day, remains the
`cornerstone for the treatment of colorectal cancer. In retrospect, this
`agent represents the very first example of targeted therapy, which
`has now become the focus of great attention in current cancer drug
`development, although the target in this case was a biochemical
`pathway and not a molecular target. These clinical observations
`increased the interest in chemotherapy and spurred the emergence of
`the R.B. Jackson Laboratories as a major source of inbred mice and
`transplantable tumors, which fostered the establishment of several
`independent screening programs around the world.
`The largest post-war program of drug development before the
`NCI became involved was at the Sloan-Kettering Institute (SKI) in
`New York. Under the leadership of Cornelius ‘‘Dusty’’ Rhoads, nearly
`the entire program and staff of the Chemical Warfare Service,
`including the pioneer clinical investigator David Karnofsky, were
`assembled into the SKI drug development program. The SKI
`investigators used the murine S180 model as their primary screen
`because it was moderately sensitive to known compounds and was
`easily transplanted with nearly 100% success, whereas in Japan,
`Yoshida used an ascites sarcoma model. Additional substantial
`programs were established at the Chester Beatty Research Institute
`in London under Alexander Haddow, the Children’s Cancer
`Research Foundation in Boston under Sydney Farber, and the
`Southern Research Institute in Birmingham, Alabama, under
`Howard Skipper. At that time, the only institutions that had
`facilities devoted to clinical drug testing in cancer patients were the
`Delafield Hospital at Columbia University, Sloan Kettering, the
`Children’s Cancer Research Foundation, and the Chester Beatty (8).
`Rhoads also attracted the interest of the pharmaceutical companies
`by offering to screen and evaluate the pharmacology of submitted
`compounds under special conditions of confidentiality. This
`practice was later adopted into the program of the NCI by Endicott
`as the very important ‘‘Commercial Discreet Agreements,’’ without
`which the industry would not have been willing to cooperate.
`As larger numbers of tumor systems became available, the
`central question for drug screeners at that time was which
`
`Figure 2. Dr. Min Chiu Li. A pioneer chemotherapist who developed new
`curative chemotherapy for metastatic choriocarcinoma and testicular cancer
`(circa 1968).
`
`These thiopurines and other related drugs have been widely used
`not only for acute leukemias but also for other diseases, such as
`gout and herpes viral infections, and as immunosuppressive agents
`in the organ transplant setting. As a result of this seminal work,
`these investigators received the Nobel Prize in Medicine in 1988.
`It was not until the middle 1950s that Charles Heidelberger and
`colleagues at the University of Wisconsin developed a drug that was
`aimed at nonhematologic cancers (26). They identified a unique
`biochemical feature of rat hepatoma metabolism in that there was
`greater uptake and use of uracil relative to normal tissue. Based on
`this observation, Heidelberger ‘‘targeted’’ this biochemical pathway
`by attaching a fluorine atom to the 5-position of the uracil pyrimidine
`base, which resulted in the synthesis of the fluoropyrimidine 5-
`fluorouracil (5-FU). This agent was found to have broad-spectrum
`
`Figure 1 Continued.
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`Figure 3. Dr. James Holland directed cooperative group studies in childhood
`leukemia (circa 1970).
`
`transplantable tumor was the best at predicting human activity.
`Among those available for use was a murine leukemia induced by
`a carcinogen, Leukemia 1210 (L1210), described by Lloyd Law at
`the NCI (27). This model system was adopted, and its kinetics were
`carefully studied by Skipper and colleagues at Southern Research
`Institute (28, 29) and later by DeVita and colleagues (30). The L1210
`model emerged as the most versatile animal tumor screening
`system and was adopted by the NCI as its primary screen. The
`research that went into the selection of the best screening system is
`reviewed in an article by Goldin and colleagues (5).
`
`The 1950s
`The 1950s were a period of undue pessimism due to the
`disappointment over the failed promise of nitrogen mustard to
`produce durable remissions. This negative view was somewhat
`offset by the discovery of corticosteroids, which were to be used in
`cancer patients but were also quickly found to produce only brief
`responses when used alone (31, 32). Although 5-FU was introduced
`into the clinic in 1958, there were few data of substance about the
`usefulness of this drug until many years later.
`However, the ferment created by the response of acute leukemia
`in children to methotrexate, and the availability of new screening
`systems,
`led to the development of the Cancer Chemotherapy
`National Service Center (CCNSC) in 1955. Although the story of
`how this program was developed is half science and half politics,
`without question it changed the face of cancer drug development
`in the world and changed the NCI and NIH irrevocably. This
`fascinating history is reviewed in detail in the excellent articles by
`Zubrod and colleagues (8) and Goldin and colleagues (5). Given the
`interest in the childhood leukemia data, the National Advisory
`Cancer Council,
`the predecessor to today’s National Cancer
`Advisory Board, convened a panel in 1952 to discuss the subject
`of a national program of cancer drug development and concluded
`that the state of knowledge was inadequate to permit the design of
`a ‘‘crash’’ program. The view that it was premature to develop such
`a program was bolstered by another review in 1954 by a committee
`of the American Cancer Society, chaired by Alfred Gellhorn, a
`prominent academician involved in cancer treatment and Director
`of Columbia’s Frances Delafield Cancer Center (33).
`
`During this time and behind the scenes, the activist and
`philanthropist Mary Lasker,
`in touch with Sydney Farber and
`impressed with the data in childhood leukemia and the antimalarial
`program, had been trying to interest the U.S. Congress in providing
`funds for such a program. In 1954, the Senate Appropriations
`Committee encouraged the NCI to develop a program and provided
`$1 million for cancer drug development. There began a tug of war
`over the proper way to use these funds between members of the
`academic community who preferred that funds be supplied for
`investigator-initiated research and those interested in cancer drug
`screening who preferred a centralized national program. Ultimately
`frustrated by the slow progress, the Senate Appropriations Commit-
`tee, at Mary Lasker’s urging, provided $5 million to NCI with a man-
`date for the establishment of the CCNSC (8). Ken Endicott became its
`first director and was to later become the fifth director of NCI. The
`entire program was set up between May and October of 1955, a
`tribute to Endicott’s organizational skills, and provisions were made
`for commercial discreet agreements with the industry, access to clini-
`cal testing facilities, and the establishment of contracts with organi-
`zations to procure mice and testing sites. In addition, resources were
`made available for pharmacology and toxicology testing and drug
`production and formulation and ultimately an organized decision
`making process called the ‘‘Linear Array with a Decision Network’’
`whereby drugs coursing through the system had to meet specific
`criteria before passing to the next step toward the clinic (34–36).
`As part of the initial development program, the CCNSC set up a
`Cancer Chemotherapy National Committee made up of NCI staff
`with representation from several national organizations as well,
`including the American Cancer Society. This committee then
`established a series of panels to further address each of the major
`issues facing those involved in cancer drug development. This effort
`was the most extensive review of requirements of drug development
`ever conducted. One of the panels of the Cancer Chemotherapy
`National Committee was the clinical panel directed by Gordon
`Zubrod. Out of this effort came the current cooperative group
`program starting with the ‘‘Eastern Solid Tumor Group’’ (now the
`Eastern Cooperative Oncology Group). Subcommittees of this panel
`also addressed the issues of the development of hormone therapy,
`statistical analysis, protocol development, and the design and
`conduct of clinical trials, many of which are still in use today but
`were not in existence in older screening programs like Shear’s at NCI.
`This ensured a wider collaborative effort and provided standardized
`techniques and a stable source of funds, heretofore unavailable, for
`the testing of new approaches to cancer treatment (37, 38).
`The CCNSC programs were supported by contracts, not grants. This
`was the first time contracts had been used at the NCI or NIH for any
`type of program, and it created considerable consternation, which was
`to dog this and a later NCI program, the Special Virus Cancer Program
`(SVCP), for several decades. The use of contracts became synonymous
`with ‘‘targeted research,’’ and was often considered anathema in the
`academic world. Regardless of the quality of the work, it was often
`discounted if it had been supported by contracts.
`In 1966, the CCNSC was incorporated into the NCI structure as
`part of the Chemotherapy Program directed by Zubrod. Now named
`the Developmental Therapeutics Program,
`it was more tightly
`linked to both the extramural clinical trials program and the NCI
`intramural program. This was done over the loud protests of the
`Deputy Director for Science at NIH, Robert Berliner, who feared the
`contamination of the NIH with a contract-supported research effort.
`By 1974, the CCNSC and its successors had grown into an annual
`budget of $68 million and was producing almost 3 million mice
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`bearing transplantable tumors and screening over 40,000 com-
`pounds a year until parts of its effort began to be supplanted by the
`pharmaceutical industry as they began to see an emerging market
`for cancer drugs that worked.
`Still, skepticism surrounded the clinical usefulness of chemo-
`therapy for cancer in the 1950s. A great deal of resources were being
`invested in a controversial effort to develop drugs, yet there was no
`evidence that drugs could cure or, for that matter, even help cancer
`patients in any stage despite some impressive antitumor responses.
`The very rare tumor of the placenta, choriocarcinoma, was the first
`to be cured. The preliminary results of a unique treatment program
`were reported in 1958 (39). The principal architect of the treatment,
`using methotrexate in an unusual way for the time, was Min Chiu Li
`(Fig. 2). The problem was no one was prepared to believe the results
`were significant because the primary site of the tumor was a
`parental hybrid tissue, subject, it was thought, to immunologic
`control. As a sign of the times, after the first two patients went into
`remission, they were presented at NCI Grand Rounds at the Clinical
`Center. The subject of the rounds was ‘‘the spontaneous regression
`of cancer’’ with the speaker being none other than Gordon Zubrod.
`Li was also told that if he persisted in using his radical treatment, he
`would have to forfeit his position at the newly opened clinical
`center. He persisted and was asked to leave (40, 41). Later, when the
`Lasker Prize was given in 1972 to investigators who had participated
`in the studies of the cure of gestational choriocarcinoma, Li shared
`his part of the prize with the person who discharged him. He later
`was to develop the first effective combination chemotherapy prog-
`rams for metastatic testicular cancer (42).
`Clinically, the 1950s ended on the same sour note on which they
`began, but eventually the creation of the CCNSC established one of the
`most successful government programs ever. Although it was often
`criticized (43–46),
`it gave birth to the multibillion-dollar cancer
`pharmaceutical industry. When he was Director of the NCI, Vince
`DeVita was often asked how many drugs came out of the program. The
`answer is, up until 1990, all of them because the CCNSC provided a
`unique central resource, unavailable in medical centers or in industry,
`
`History of Cancer Chemotherapy
`
`Figure 5. Dr. Emil J. Freireich during his days at NCI (circa 1964).
`
`to test, develop, and produce drugs whatever the source. Drugs that
`were not identified in the primary screen itself often were evaluated in
`the ancillary tumor systems, and the necessary toxicology and
`pharmacology for regulatory approval for many drugs was done under
`the auspices of the CCNSC. Clinical studies were then often done
`under contract with the NCI or in one of the national cooperative
`groups. None of this would have been possible in the academic
`medical centers as even today the kinds of resources are not available
`at the majority of university cancer programs nor were these studies
`considered to be worthy of investigator-initiated research.
`
`The 1960s—The Concept of Cure
`In the 1960s, medical oncology did not exist as a clinical
`specialty. Those who were given the task of administering
`chemotherapy at most medical centers were regarded as under-
`achievers at best. 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. A few vignettes will illustrate this point rather graphically.
`At the medical institution where Vince DeVita began his career,
`the ‘‘chemotherapist’’ was an endocrinologist, Louis K. Alpert, who
`had published one of the early reports on the use of nitrogen
`mustard in lymphomas and administered chemotherapy as a
`sideline. Because of his stern and pointed visage, and because he
`appeared when chemotherapy was to be administered, he was
`referred to by the house staff and the faculty as ‘‘Louis the Hawk
`and his poisons,’’ a designation he took gracefully. Unfortunately,
`poison was the term in general use for anticancer drugs.
`The Francis Delafield Hospital, although connected with
`Columbia University College of Physicians and Surgeons, was
`ultimately denied access to residents and interns from Columbia
`because two successive chairmen of medicine, Robert Loeb and
`Stanley Bradley, did not want their house staff exposed to cancer
`patients receiving these cancer poisons, although their mentor
`would have been the distinguished Alfred Gellhorn. As Alfred
`Gellhorn recently recounted to the authors,1 the otherwise great
`clinician Loeb, a giant in the field at the time, had a blind
`spot when it came to caring for cancer patients and testing
`
`Figure 4. Dr. Emil Frei (circa 1965).
`
`1 Interview with Dr. Alfred Gellhorn (November 26, 2007).
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`chemotherapy. He was fond of saying to Gellhorn, rather openly,
`‘‘Alfred, you belong to the lunatic fringe.’’ The Delafield Hospital
`program, the first example of a university-based cancer center, with
`many illustrious graduates,
`including Bernard Weinstein, Elliot
`Osserman, John Ultmann, Jim Holland, Paul Marks, Franco Muggia,
`Helen Ranney, and Jack Davidson, was closed in 1971. The leaders
`at Delafield provided the nidus to create a new cancer center at
`Columbia in 1974, after the cancer act in 1971 provided a mandate
`to create new university-based cancer centers.
`At Yale, the first institution to test chemotherapy in humans in
`the modern era, the chemotherapist Paul Calabresi, a distinguished
`professor and founding father in the field, was forced to leave
`because he was involved in too much early testing of new
`anticancer drugs, an exercise as unpopular with the faculty and
`house staff at Yale as it was at Columbia.
`At the Clinical Center of the NCI, where so many of the early
`breakthroughs with chemotherapy occurred,
`the well-known
`hematologist George Brecher, who read all the bone marrow slides
`of the leukemic patients, routinely referred to the Leukemia Service
`as the ‘‘butcher shop’’ at rounds.
`And these are only the stories that can be told. It took plain old
`courage to be a chemotherapist in the 1960s and certainly the
`courage of the conviction that cancer would eventually succumb to
`drugs. Clearly, proof was necessary, and that proof would come in
`the form of the cure of patients with childhood acute leukemia and
`in adults with advanced Hodgkin’s disease.
`By 1960, the L1210 leukemia system had been established as both
`the primary screen and the model for treating acute leukemia. Work
`on L1210, childhood acute leukemia, and Hodgkin’s disease was
`going on in parallel. At the turn of the decade, complete remissions
`were occurring in about 25% of children with leukemia, but with
`
`single agents, they were brief, measured in months. Several
`institutions were cooperating in protocols with a design that hinted
`at cure, not palliation, as an end point. Such studies were in progress
`at RPMI in Buffalo under Jim Holland (Fig. 3), St. Jude’s in Memphis
`under Don Pinkel, Boston Children’s Cancer Center under Sydney
`Farber, Memorial Sloan-Kettering Hospital under Joe Burchenal,
`and the Clinical Center program at the NCI under Emil (Tom) Frei
`(Fig. 4) and Emil (Jay) Freireich (Fig. 5) (46–49). Gordon Zubrod,
`then director of the National Chemotherapy Program, the organizer
`of this effort, played a major role in linking the work of Howard
`Skipper (Fig. 6) on L1210 at Southern Research Institute with the
`clinical programs at the Clinical Center of the NCI and elsewhere.
`A major breakthrough occurred for both leukemia and Hodgkin’s
`disease with the discovery of the activity of the plant alkaloids from
`Vinca rosea at the Eli Lilly Company (50) and discovery of the activity
`of ibenzmethyzin in Hodgkin’s disease (soon to be renamed pro-
`carbazine) by Brunner and Young (51) and DeVita and colleagues (52).
`Furth and Kahn (53) had shown that a single implanted leukemic
`cell was sufficient to cause the death of an animal. At Southern
`Research, Skipper had suggested that to cure L1210, it was necessary
`to eradicate the last leukemia cell because back extrapolations of
`survival after treatment suggested that one surviving cell was
`sufficient to kill a mouse. He offered the ‘‘Cell Kill’’ hypothesis, which
`stated that a given dose of drug killed a constant fraction of tumor
`cells not a constant number, and therefore success would depend on
`the number of cells present at the beginning of each treatment (54).
`This observation changed the existing approach to dosing in the
`clinic in favor of more aggressive use of chemotherapy. In L1210, the
`schedule of administration of drugs was also proving to be
`important. Finally, combinations of drugs, an anathema in medicine
`at the time, were superior to sin