Joseph Holland Burchenal, one of the true pioneers of cancer chemotherapy and past president of the American Association for Cancer Research (AACR), died from heart failure on March 8, 2006, in Hanover, New Hampshire. He was 93. 
Dr. Burchenal was born December 21, 1912, in Milford, Delaware, and attended Exeter Academy in New Hampshire. As a boy, he showed an early interest in science and chemistry. But it was the loss of his mother to osteogenic sarcoma during his undergraduate years at Princeton University that launched his career in cancer research.
Following his graduation from Princeton, he attended the University of Pennsylvania where he received his medical degree. During the 1930s, Dr. Burchenal became interested in childhood leukemia while working with hematologist Dr. Walter Baetjer at the Pediatric Service of Union Memorial Hospital in Baltimore, Maryland. At the time, antibiotics were being used to treat pneumonia and other infectious diseases. He reasoned that if chemistry could be used to treat such diseases, perhaps chemically based treatments for cancer would work as well.
During World War II, and immediately thereafter, Dr. Burchenal served as Chief of Infectious Disease at the Harvard Fifth General Hospital in Northern Ireland, England, and France; and as Chief of Tropical Medicine at the Walter Reed Hospital, Washington, DC. Upon discharge from the military, Dr. Burchenal joined the staff of the Memorial Hospital and the newly established Sloan-Kettering Institute for Cancer Research, where he remained until his retirement in 1983. During his tenure there, he was vice president of the Sloan-Kettering Institute and was head of its applied therapy laboratory. He was also a professor of medicine at Weill Medical College of Cornell University, Ithaca, New York.
Dr. Burchenal began his career in the late 1940s at what is now the Memorial Sloan-Kettering Cancer Center in New York City. At that time, standard treatment for cancer patients was surgery and radiation. Little hope could be offered for disease that went beyond a small isolated tumor, particularly after it had spread to other sites.
Dr. Burchenal was among a small coterie of physicians who believed that another approach might make a difference—the use of drugs. Many thought the disease was so complex, even incomprehensible, that this notion was not even worth trying. Indeed, when the nascent group of “neochemotherapists” came together for scientific meetings, no more than 40 would show up.
Some of the earliest discussions of this group focused on cancers of the blood, particularly the leukemias and lymphomas. At the time, such a diagnosis was considered a veritable death sentence, with life expectancy generally measured in weeks. But some speculated that cancer might be controlled with the use of chemicals that could block the synthesis of DNA, and experiments began focusing on a variety of compounds designed to attack cancer cells at the genetic level. Among the chemicals under study were nitrogen mustard and other alkylating agents, as well as chemicals that targeted purines and pyrimidines and their nucleotides, and a new class of antimetabolites that interfered with their synthesis or functions.
In 1948, Dr. Burchenal began studies with a drug developed by Drs. George Hitchings and Gertrude Elion at Burroughs Wellcome in New York—2,6-diaminopurine—an antagonist of folic acid required for DNA synthesis. At first, animal experiments in mice yielded encouraging results; however, the toxicity of the drug made it unusable for humans. To reduce the side effects of the drug, Drs. Hitchings and Elion modified the compound to create 6-mercaptopurine (6-MP).
In 1953, Dr. Burchenal and colleagues reported in a landmark article in Blood that the drug, in a first clinical trial, produced “good clinical and hematologic remissions” in one-third of 45 children with acute leukemia; another 10 “showed partial remissions and clinical improvement.” The drug was subsequently approved by the Food and Drug Administration and marketed under the name Methotrexate.
Partly based on their synthesis of 6-MP, Drs. Hitchings and Elion were subsequently awarded Nobel prizes. Some thought that Dr. Burchenal should have shared in that award. “It was 6-MP that started them on the road to synthesis of a lot of other interesting and useful compounds,” said Dr. Irwin H. Krakoff. “Had it not been for Joe's demonstration of its activity in leukemia, it would have languished on the laboratory shelf.”
Although Methotrexate extended life by months, few were actually cured. So Dr. Burchenal and colleagues tried another strategy, using a combination drugs to attack the growth of cancer cells along multiple fronts. These included anthracyclines, which inhibit DNA replication by inserting themselves between base pairs of the DNA/RNA strand, and oral Vinca alkylating agents, such as vincristine, a derivative of the periwinkle family, which disrupt cell division. By the early 1960s, the use of “drug cocktails” increased the five-year survival rate for blood cancers from near zero to about ∼80%.
In the late 1950s, Dr. Burchenal turned his attention to solid tumors. His collaborations with Drs. Denis Burkitt, Herbert Oettgen, and Peter Clifford yielded the first meaningful treatments for children in East Africa suffering from a new type of lymphoma that presented as a jaw tumor, subsequently called “Burkitt's tumor.” Before their studies, the treatment of choice for lymphoma was radiation, which was unavailable where Dr. Burkitt was working in Kampala, Uganda. Speculating that drugs might provide a workable alternative to attack this fast-growing B-cell tumor, the Sloan-Kettering team developed a protocol involving combination chemotherapy that included the anticancer drug cyclophosphamide. “The children responded very well, and some of them were eventually cured,” said Dr. Oettgen, who was enlisted by Dr. Burchenal to move to Nairobi to begin this line of treatment.
During a scientific conference on Burkitt's lymphoma, held in 1965 in Kampala, a dozen children who had been cured of Burkitt's lymphoma by chemotherapy were brought from their villages and presented to the group by Dr. Burkitt. At the concluding banquet, Sir Alexander Haddow, then president of the Chester Beattie Institute in England, said that no one had done more than Dr. Burchenal to bring about a cure for these children. “And then he said,” Dr. Oettgen recalled, “that he could think of no better way to describe Dr. Burchenal's life than by saying it had always been a pledge to the future.” In 1972, Dr. Burchenal, along with Dr. Burkitt and 14 others, were honored with the Lasker Award for work in clinical medical research.
Aside from his accomplishments as a physician and scientist, Dr. Burchenal served as a mentor to many others who one day would make their mark in the field. The chemotherapy program at Sloan-Kettering, established by Dr. David A. Karnofsky and Dr. Burchenal, was one of the first of its kind in the nation. Dr. Burchenal also helped support the training of physicians interested in pursuing a career in pediatric oncology.
“I feel I owed him so much, he was such a wonderful person to me,” said Dr. M. Lois Murphy, who served as chair of the pediatrics department at Cornell in the mid-1950s. “He appreciated training in pediatrics when a lot of other people at Memorial did not.”
“Everybody liked Joe,” said Dr. Bayard Clarkson, member and head of the Laboratory of Hematopoietic Cell Kinetics at Memorial Sloan-Kettering Cancer Center, former AACR president, and another individual mentored by Dr. Burchenal. “His enthusiasm for the cause was infectious, and coupled with his intrinsic friendliness, cheerful nature and humility, it is small wonder that he was universally popular.”
Dr. Burchenal was an avid skier and outdoorsman who, even into his 80s, loved hiking and mountain climbing, particularly the 46 peaks in the Adirondacks taller than 4,000 feet, making him part of an exclusive club of “46ers.” He trekked to Scotland, Wales, Peru, New Zealand, and Nepal, where he climbed the Himalayas. To keep in shape, he would always use the stairs instead of the elevator even though, in his later years, his office was on the 11th floor of the old Memorial building.
During his career, Dr. Burchenal continued to study a variety of chemotherapeutic agents and their combinations, and he authored more than 700 peer-reviewed publications. He served in a variety of important advisory roles, and as an officer and committee member for many professional organizations.
Aside from serving as President of AACR from 1965 to 1966, he was a member of the Board of Directors from 1963 to 1968, and was elected an Honorary Member of the Association in 1987. In 1996, the AACR-Joseph H. Burchenal Clinical Research Award was established in his honor as a major figure in clinical cancer research. This award is presented annually to a researcher who has made significant contributions to clinical care in the field of cancer. In addition to his AACR service, Dr. Burchenal was an advisor to U.S. Senate committees, the National Cancer Institute, and many other professional organizations.
Among his accomplishments in the public arena, Dr. Burchenal, along with several other leading cancer researchers, including Drs. James Holland and Mathilde Krim, coauthored a report calling for a national crusade on cancer. That report eventually led to the National Cancer Act, signed into law in 1971 by President Richard Nixon.
Dr. Burchenal received a host of awards, including the Alfred P. Sloan Award (1963), Prix Leopold Griffuel (1970), the David A. Karnofsky Memorial Award of the American Society of Clinical Oncology (1974), the James Ewing Award (1975), the American Cancer Society Annual Award (1982), the Return of the Child Award of the Leukemia Society of America (1986), and the Distinguished Scientific Award of American Society of Clinical Oncology (1994).
Dr. Burchenal is survived by his wife of 58 years, the former Joan Barclay Riley. The couple lived in Darien, Connecticut, before moving to New Hampshire two years ago. Margaret Pembroke Thom, his first wife, died in 1943. He is also survived by three sons, Caleb W. (Denver, CO), Dr. David H. (an internist, Stonington, CT), and Dr. J.E.B. (a cardiologist, Denver, CO); three daughters, Holly Nottebohm (Guatemala City), Jody Nycum (Denver, CO), and Bobbie Landers (Darien, CT); a sister, Betty Maxfield (Wolfeboro, NH); 16 grandchildren; and 8 great-grandchildren.
Contributors to this tribute include Dr. Bayard D. Clarkson, Memorial Sloan-Kettering Cancer Center, New York, New York, and Dr. Margaret Foti, AACR.
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