Backed by a robust Federal government grant, the NCI was the right place to be for adventurous researchers. Drs. Frei and Freireich had everything they needed: A new clinic, lots of empty beds, a vast laboratory and the enthusiastic support of the Institute's Director, Dr. Zubrod. The two researchers decided to focus their clinical activities on acute lymphocytic leukemia (ALL) term in children. Asked why they chose leukemia, Dr. Frei said, “There were several reasons. One is that Dr. Jim Holland, who had been there before us, started the program in leukemia, so we inherited his patients, if you will.”

Frei was one of the founders of the Acute Leukemia Group B, which later evolved into the Cancer and Leukemia Group B. He served as the group chair for 16 years, from 1956 to 1963 and again from 1981 to 1990.

At the time, scientists knew very little about the biochemical and physiological processes of normal and cancer cells or the role of genes in controlling the pathways of metabolism. Anti-leukemic drugs were among the first to be tested because animal models were available. Early studies initiated in the laboratory of Lloyd Law at the NCI, a unit of the National Institutes of Health (NIH), involved the use of an inbred mouse strain (DBA/2) originally obtained from The Jackson Laboratories in Bar Harbor, Maine. This mouse strain was genetically pre-disposed to develop cancer. When Law painted the skins of these mice with a carcinogen, the mice developed lymphocytic leukemia within 2 to 3 months. He then collected fluid from the peritoneal cavity of the mice and grew the lymphoblastic cells in vitro, labeling those L12l0 cells (L was for Law). This cell line has been and still is extensively used in cytotoxicity assays for screening chemotherapeutic compounds before administering them to animals.[6,7]

Additional studies showed that leukemic mice given multiple treatments of 6-MP eventually developed cells that were resistant to the drug. Fortunately, further mouse studies in Law's laboratory showed that treatment with another drug readily killed the resistant cells. Drug resistance to one drug could be overcome by the use of another drug. From these preclinical studies, the concept of combination chemotherapy was developed. Law communicated his successful leukemia treatment regimen to two NCI clinician-investigators, Emil J. Freireich and Emil Frei, who worked in NCI's chemotherapy program. In 1962, their collaboration led to the development of a regimen to treat childhood leukemia patients with a combination of four drugs.[8]

Working on limited scientific “leads” in ALL, Drs. Frei and Freireich attempted to sort out the “chaos in the field” at the time, which was largely a compilation of anecdotes; prospective experimental designs were lacking. At the time, there were two agents — 6-mercaptopurine and methotrexate — that showed activity in ALL. At the insistence of Dr. Zubrod, the two young researchers wrote protocols and defined what complete response was in advance, thus defining how to proceed tactically.

It was a watershed event in experimental trial design; however, not without controversy. Dr. Frei explained, “It was controversial because it was felt that we were making patients fit a protocol, whereas you should instead fit the protocol to the patient. It sounds like a compelling argument, but if you don’t really know what you’re doing, you need to have a prospective protocol that asks a question and gets an answer.”

Within a year, Dr. Frei was named Chief of NCI's Leukemia Section and later, Chief of Medicine. Frustrated by the short-term remissions achieved in ALL that they were seeing with single-drug therapies, Drs. Frei, Freireich and Holland began testing combinations of two or more agents to attack the various aspects of leukemia cells’ growth. Testing ideas through controlled experimentation requires a thirst for innovation and change, often in the face of a stubborn status quo. Dr. Frei and his colleagues persevered, marshaling in a paradigm shift in oncology therapeutics: Combination chemotherapy term.

The team also worked on the difficult problem of chemotherapy-related bleeding by demonstrating that the infusion of platelets would allow larger, more effective doses of chemotherapy to be delivered safely.

In 1965, Dr. Frei moved to The University of Texas MD Anderson Cancer Center in Houston, where he served as Associate Director of Clinical Research and Chair of the Department of Experimental Therapeutics. He joined Dana-Farber Cancer Institute in 1972, serving as Physician-in-Chief, succeeding the Institute's founder, Sidney Farber, MD, who died later that same year. Just 1 year later, Dr. Frei was named Dana-Farber's Director and Professor of Medicine at Harvard Medical School.

Dissatisfied with the short-term ALL remissions produced by single-drug therapies, Drs. Frei, Freireich, James Holland, MD, and others began testing combinations of two or more agents to attack multiple aspects of leukemia cells’ growth. The research was driven by Dr. Frei's ability to see promise where others saw discouragement. When Dr. Frei and his colleagues began these combinations in patients, only a few were cured. Undeterred, he found lessons in these survivors that could improve therapies in the next round of trials. He demanded the same single-mindedness in those he worked with. The Frei-Freireich team also tackled the problem of chemotherapy-induced bleeding and showed that infusions of blood platelets allowed chemotherapy to be given safely in larger, more effective doses. Today, combination chemotherapy and platelet transfusions result in complete and permanent cures for three of every four children with ALL. The method is credited as a very significant advance in saving the lives of patients with cancer.

Dr. Frei moved to the M.D. Anderson Cancer Center in Houston in 1965, where he served as associate scientific director of Clinical Research and chaired the Department of Experimental Therapeutics. In 1972, he joined Dana-Farber as physician-in-chief, succeeding the Institute's founder, Sidney Farber, MD. In 1973, he became director of Dana-Farber and professor of Medicine at Harvard Medical School.

With Dana-Farber colleagues Arthur Skarin, MD, and George Canellos, MD, he developed a therapy for adults with non-Hodgkin lymphoma — one of the first chemotherapy regimens to produce a significant cure rate for the disease. He joined fellow Dana-Farber researchers in initiating the use of chemotherapy, surgery and radiation therapy as a primary treatment for osteogenic sarcoma, a bone cancer of young adults. In the mid-1970s, he and his associates developed and tested drug combinations that boosted survival rates for breast cancer patients. He also worked with Dana-Farber investigators to pioneer the use of bone marrow transplants for various types of cancers.

Under Dr. Frei's stewardship, Dana-Farber became one of the world's premier centers for cancer care and research in children and adults. Dana-Farber's staff increased from 150 at his arrival to 900 by the end of the decade.

“Tom Frei was one of a handful of physicians who developed combination chemotherapy for cancer and produced the first cures of childhood leukemia,” said David Nathan, MD, president of Dana-Farber from 1995 to 2000. “His was a massive contribution to medicine. Patients and trainees will remember him with deep respect.”

For a generation of workers in the Longwood Medical Area, Dr. Frei was a familiar sight, pedaling his bike to and from Dana-Farber. His sense of humor is legendary at Dana-Farber.

He most recently lived in Chicago. Dr. Frei was married to Elizabeth (Smith) Frei from 1948 until her death in 1986. He later was married to Adoria (Brock) Frei from 1987 until her death in 2009. Dr. Frei is survived by his five children, Mary, Emil (and his wife, Lauren), Alice, Nancy, and Judy (and her husband, Larry Howe) and by 10 grandchildren.

In tribute, Dana-Farber President Edward J. Benz, Jr., MD, said, “This approach has led to cures in many patients with cancer. The majority of patients with certain forms of childhood leukemia, Hodgkin disease, testicular cancer and some other cancers can now expect to live long, high-quality lives because of his contributions.”

Dr. Frei published more than 500 papers in scientific and professional journals and was the recipient of numerous awards and honors. In 1972, he received the Lasker-DeBakey Clinical Medical Research Award from the Lasker Foundation “for his outstanding contribution in application of the concept of combination chemotherapy for lymphoma and acute adult leukemia.” Other awards included the Jeffrey A. Gottlieb Memorial Award (1978); NIH Distinguished Alumni Award (1990); Fellow, American Academy of Arts and Sciences (1999); Pollin Prize for Pediatric Research (2003); and AARC Lifetime Achievement Award (2004).

Dr. Frei described two types of clinical cancer researchers, namely “investigators” versus “discoverers.”[9] The investigators proceed in a very orderly fashion, are esteemed by their peers, typically succeed (at least in answering the often rather ordinary question being addressed by their work), but produce, at most, single step advances and don’t create new paradigms. Discoverers, on the other hand, follow a path of inquiry, which often seems disordered, tend not to be esteemed by their peers, often fail, but, on occasions where they do succeed, produce multi-step advances and create new paradigms. Dr. Frei's point was that the clinical oncology research establishment would be well-advised to be more supportive of the work of discoverers.

Since that 1981 speech, the best example of discovery-oriented clinical research comes from gastroenterology — the central role of bacterial infection (Helicobactor pylori) in peptic ulcer disease. We’ve had some breakthroughs of lesser magnitude in oncology: Anti-Her2 treatment of breast cancer, anti-CD20 in lymphatic neoplasms, tyrosine kinase inhibitors, etc.

Dr. Frei moved to the M.D. Anderson Cancer Center in Houston in 1965, where he served as associate scientific director of Clinical Research and chaired the Department of Experimental Therapeutics. In 1972 he joined Dana-Farber as physician-in-chief, succeeding the Institute's founder, Sidney Farber, MD. In 1973, he became director of Dana-Farber and professor of Medicine at Harvard Medical School.

With Dana-Farber colleagues Arthur Skarin, MD and George Canellos, MD, he developed a therapy for adults with non-Hodgkin lymphoma, one of the first chemotherapy regimens to produce a significant cure rate for the disease. He joined fellow Dana-Farber researchers in initiating the use of chemotherapy, surgery and radiation therapy as a primary treatment for osteogenic sarcoma, a bone cancer of young adults. In the mid-1970s, he and his associates developed and tested drug combinations that boosted survival rates for breast cancer patients. He also worked with Dana-Farber investigators to pioneer the use of bone marrow transplants for various types of cancers.

Under Dr. Frei's stewardship, Dana-Farber became one of the world's premier centers for cancer care and research in children and adults. Dana-Farber's staff increased from 150 at his arrival to 900 by the end of the decade.

Even still, in a career as lush with accomplishments, awards, positions, and publications as Dr. Frei's, it was his patients that mattered most. His work helped bring about the first complete cures for pediatric leukemia patients and led to more effective treatments for adult malignancies ranging from breast cancer to bone cancer. In his early days working in childhood leukemia, when the outcomes were still grim, he remarked, “Children are a challenge and also a joy to work with.” That he found joy in caring for desperately ill-children is what his colleagues, friends, and patients will best remember him for.

In tribute, Dana-Farber President Edward J. Benz, Jr., MD, said, “This approach has led to cures in many patients with cancer. The majority of patients with certain forms of childhood leukemia, Hodgkin disease, testicular cancer and some other cancers can now expect to live long, high-quality lives because of his contributions.” On Monday, February 12, 2007 Senator Dean Heller from Nevada stood on the floor of the U.S. Senate and said, “Madam Speaker, I rise today to pay tribute to Dr. Emil Frei III, a pioneer in cancer treatment, one of the world's foremost oncologists and a leader in medical education. His exceptional career deserves the highest commendation and praise.”

The oncology community also rises in tribute. Hear, hear, Dr. Frei.

Footnotes