Dr. Emil Frei III, an oncologist whose trailblazing use of combination chemotherapy — in which anticancer drugs are administered simultaneously rather than singly — helped make certain cancers curable for the first time, died on Tuesday at his home in Oak Park, Ill. He was 89.
His daughter Judy Frei confirmed the death.
Combination chemotherapy is now a standard treatment for a wide range of cancers, including breast, bone and testicular cancers, and has been credited with saving millions of lives worldwide.
A clinician, researcher and administrator, Dr. Frei (pronounced "fry") held senior leadership positions at three prominent cancer centers: the National Cancer Institute, part of the National Institutes of Health; the M. D. Anderson Cancer Center in Houston; and the Dana-Farber Cancer Institute in Boston.
At his death, Dr. Frei was the emeritus director and emeritus physician-in-chief of Dana-Farber. He was also the Richard and Susan Smith distinguished professor of medicine emeritus at Harvard Medical School.
When Dr. Frei began his research at midcentury, chemotherapy with even a single drug, much less multiple ones, was considered a treatment of last resort.
"It was known that these drugs were cell-killers: some of them were derived from mustard gas," Dr. Harold E. Varmus, the current director of the National Cancer Institute and a winner of the 1989 Nobel Prize in Physiology or Medicine, said Friday. "They were developed initially as toxic agents, not different from drugs that were used in warfare."
In the mid-1950s, Dr. Frei, along with Dr. Emil J. Freireich, a colleague at the National Cancer Institute, and others, began investigating a multipronged assault on childhood leukemia that entailed using these drugs in combination, with each attacking a different aspect of cancer-cell physiology.
As the two men and their colleagues found, administering a cocktail of anticancer drugs let each drug be given in smaller quantities. This mitigated the drugs' toxic effects on the patient without diminishing their combined attack on the cancer.
"If you give 60 percent of each dose, it's the same as giving 100 percent of one or the other," said Dr. Freireich, who is now at M. D. Anderson. "But the effect on the tumor is additive."
When Dr. Frei and Dr. Freireich began their work, childhood leukemia was invariably fatal. By 1965, after a decade of clinical trials and refinements, the methods they devised, which involved combining as many as four drugs, had increased the survival rate to about 40 percent five years after treatment.
Today, childhood leukemia has a long-term survival rate of more than 80 percent.
"There are recurrences, but the incidence is low," Dr. Freireich said. "These are lifetime cures. Compared to the general population, their survival rate is the same as for people who hadn't had leukemia."
The two men then applied their approach to Hodgkin's disease, also rendering it curable in many cases.
Emil Frei III, familiarly known as Tom, was born in St. Louis on Feb. 21, 1924.
In 1898, his paternal grandfather founded Emil Frei & Associates, a stained-glass company in the city that is still well known, and Emil III was expected to pursue the family calling. But he became interested in medicine in his youth after reading "Rats, Lice and History," Hans Zinsser's 1935 "biography" of typhus.
Serving in the Navy in World War II, he was sent for premedical studies at Colgate University and medical studies at Yale, from which he earned an M.D. in 1948. He later served with the Navy Medical Corps in the Korean War.
Dr. Frei joined the staff of the National Cancer Institute in the mid-1950s. He was later chief of the leukemia section and chief of medicine there.
In 1965, he moved to M. D. Anderson, where he was the associate scientific director of clinical research and the chairman of the division of experimental therapeutics. He joined the institute now known as Dana-Farber as physician in chief in 1972 and became its director the next year.
At all three institutions, Dr. Frei also trained a generation of researchers and clinicians.
Dr. Frei's first wife, the former Elizabeth Smith, whom he married in 1948, died in 1986; his second wife, the former Adoria Smetana Brock, whom he married in 1987, died in 2009. Besides his daughter Judy, his survivors include three other daughters, Mary, Alice and Nancy Frei; a son, Emil IV; a brother, Bob; and 10 grandchildren.
In his Pulitzer Prize-winning book, "The Emperor of All Maladies: A Biography of Cancer," published in 2010, the doctor and author Siddhartha Mukherjee wrote of Dr. Frei making rounds on a pediatric oncology ward.
"He was charming, soft-spoken and careful," Dr. Mukherjee wrote. "To watch him manage critically ill children and their testy, nervous parents was to watch a champion swimmer glide through water — so adept in the art that he made artistry vanish."
One of those children was Edward M. Kennedy Jr., a son of the Massachusetts senator. In 1973, at 12, young Ted Kennedy lost a leg to osteosarcoma, an aggressive form of bone cancer.
A patient of Dr. Frei's at Dana-Farber, he underwent intensive chemotherapy for nearly two years afterward. He has remained free of cancer ever since.
"I honestly believe that Dr. Frei saved my life," Mr. Kennedy, now 51 and a lawyer and disability rights advocate in New Haven, said in an interview on Thursday. "My father obviously had incredible resources in terms of being able to identify the most capable people. And of all the people in the world, he asked Dr. Frei to take care of me."
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