When Emil “Tom” Frei and Emil “Jay” Freireich came to work at NCI in 1955, the time was right for a major breakthrough in treatment research on cancer, a disease previously thought to be incurable. When they left NCI 10 years later, they had demonstrated that at least one form of cancer, childhood leukemia, indeed could be cured. In the intervening years, their work set the standard by which all other clinical research, even today, is measured.
For that contribution, the two researchers were honored with the first NIH Distinguished Alumni Award, presented at a symposium in their honor this week. The award, given by the NIH Alumni Association, is to be an annual event.
“We were particularly lucky in time and place,” said Frei, who was 31 when he came to NCI. “The clinical center was new, and believe it or not, there was empty laboratory space. The goal here was research. You were expected to do new things. We were ideally positioned to do leukemia research.”
“Many of us in clinical research don’t live to see the results of our research. It’s a privilege to be alive to witness the fruits of our work,” said Freireich, who was 28 when he joined NCI. Frei and Freireich both left NCI for M.D. Anderson Cancer Center in 1965, where Freireich is now director of the adult leukemia research program. Frei is now director and physician-in-chief of the Dana-Farber Cancer Institute.
In 1955, less than 1 percent of childhood leukemia patients lived long enough to be considered cured. While a few new drugs had shown antileukemic activity as single agents, most patients who responded relapsed quickly due to drug resistance, which made single agent chemotherapy useless for long term control of the disease.
Patients also suffered infections and complications that were as life-threatening as the disease itself.
Despite a consensus among cancer specialists that there was no cure for the disease, Frei and Freireich persisted in their research.
“The process of discovery is rejecting paradigms that have already been proved,” Freireich said later.
Working together and with their trainees–who now are spread around the U.S.–Frei and Freireich discovered they could combine drugs and use larger doses for shorter periods of time, which made the drugs safer and more effective. They advocated longer rest periods between treatments to allow normal healthy cells to recover.
Many of the methods now used to treat opportunistic infections were developed by Frei & Freireich. They developed the method to prevent bleeding by transfusion of blood platelets. They showed how platelet transfusion could ward off the destruction of platelets by the immune system. They proved that infections could be stopped by transfusions of white blood cells. They advocated the use of antibiotics and germ-free rooms for patients.
“These are things we now take for granted,” said Div. of Cancer Treatment Director Bruce Chabner, who presented the award to the researchers.
Much of what is known today about remission induction in the treatment of leukemia may be traced to their landmark 1962 study on the combination treatment VAMP–vincristine, amethopterin, mercaptopurine and prednisone. That research–besides providing curative treatment for a previously incurable disease–also led to the development of treatments for metastatic breast cancer, and curative treatments for Hodgkin’s disease, non-Hodgkin’s lymphoma, metastatic germ cell tumors, osteogenic sarcomas, rhabdomyosarcoma and Ewing’s sarcoma.
Today, the five-year survival rate for children with acute lymphocytic leukemia now exceeds 75 percent.
For their work in chemotherapy, Frei & Freireich were given the Albert Lasker Award in 1972 and in 1983, shared the General Motors Research Foundation’s Charles Kettering Prize.
“They opened a whole new era in for those of us interested in cancer research by proving that drugs do have a curative effect,” said Paul Marks of Memorial Sloan-Kettering Cancer Center.
After moving to M.D. Anderson, the two researchers continued their work in adult leukemia, examining the use of combination therapy. They developed a regimen of cytoxan, oncovan, arabinoside and prednisone (COAP), which was demonstrated to cause complete remissions in half of the 300 patients treated, with an average duration of one year. Between 15 to 20 percent of the patients were cured.
At the symposium to honor Frei & Freireich Vincent DeVita, physician-in-chief at Memorial Sloan-Kettering and former NCI director, put the researchers’ accomplishments in historical perspective:
“Think back about the attitude toward cancer at that time. It was widely considered an incurable disease. The major question was whether you could palliate patients with chemotherapy, and was it worth it? Of course, there was no cure.
“I remember being quite stunned when I arrived and I saw my first remission with chemotherapy…. The basic principles for the use of chemotherapy were established here under Frei and Freireich.”
Another legacy of Frei & Freireich was the clinical associate program, which was the first oncology training program in the country.
DeVita also credited the two with causing excitement over cancer research. “Their accomplishments directly led to the legislation creating the National Cancer Program,” he said.
DeVita, who was one of the last Frei & Freireich clinical associates, said he learned from Frei that “you didn’t have to be older or more senior” to accomplish a great deal.
In 1965, DeVita left NCI for what was supposed to be a two-year stint at Yale, but he returned after a year. “I was frustrated because the advances I saw at NIH were not being used in the hinterlands. I saw people who needed platelets but weren’t getting them because platelets were not supposed to work.”
Freireich, recognizing the impermanence of scientific achievements, said that as late as 1975, he participated in scientific meetings “where the question was, ‘Does chemotherapy cure leukemia?'” As some leukemia patients have been known to relapse many years later, it is important to investigate the mechanisms of relapse and to study whether there is a total cure, he said.
“In my personal practice, I have a young woman who was cured, went on to get married and have children, and 12 years later she came back with a disease similar to the disease she had earlier,” Freireich said.
Reviewing his work since leaving NCI, Freireich said leukemia is still an important disease. “Twenty-five years later, AML is much closer to opening the door to common malignancies that it was 25 years ago. My contention is that AML is still the most important disease for understanding common malignancies. The next 25 years will be even more exciting and I hope I’ll be here to talk about it.”
Frei traced the evolution of combination chemotherapy from 1965 to the present. The development of the VAMP regimen for ALL led to the development of the MOPP regimen for Hodgkin’s disease. That led to CHOP for non-Hodgkin’s lymphoma, which led to ara-C-D for AML, then CMF as adjuvant for breast cancer, then PVB for testicular cancer, then ABVD for Hodgkin’s disease, then AM for adjuvant treatment of osteogenic sarcomas, then PFL for head and neck cancers, then M-VAC for neoadjuvant treatment of bladder cancer, which has led to 5FU/L for adjuvant treatment of colon cancer.
Frei discussed a study at Dana-Farber of PFL vs. previous platinum based regimens for treatment of stage 4 head and neck cancer. PFL has a response rate of 68 percent, compared to 29 percent for the controls, after follow-up of two years.
Frei outlined his “near future,” “intermediate future” and “long term” predictions for advances in cancer research:
- Near future (up to five years):
- the neoadjuvant approach is going to be successful in head and neck and possibly bladder cancer.
- molecular knowledge on drug resistance, which has taken off in the last five years, will continue to make gains.
- Gains will be made in research on solid tumor microenvironments, monoclonal antibodies, growth factor receptors, specificity, humanization of monoclonal antibodies, membrane receptors and lymphocytes including LAK, TIL and bioengineered ricin-related molecules.
- Intermediate future (five-10 years) :
- Advances will be made in x-ray crystallography, novel targets such as oncogenes, oncogene products and signal transduction, antiviral agents, cell cycle and antiangiogenesis.
- Long range (10-25 years) :
- Advances will be made in antisense transcriptional control, invasion and metastasis, splicing and tumor suppressor genes.
“We’ve got to think of cancer research as a science, and we need to give the investigator the resources for independent, creative work,” Frei said. At the symposium, James Griffin of Dana-Farber discussed his work with growth regulation of leukemia, and Donall Thomas of Fred Hutchinson Cancer Research Center discussed his work on bone marrow transplantation.