News
Study Parameters From September 1989 through December 1993, approximately 1,000 ALL cases and 1,000 controls (in six mid-Atlantic and midwestern states) will be evaluated. These will be approximately half of the population being studied in the CCSG protocol. Evaluation parameters include questioning parents about EMF exposures, such as use of electric blankets; diagramming configurations of neighborhood power lines and residential wiring; taking spot and 24-hour measurements of EMFs in areas frequented by the children (both within and outside homes and schools); and conducting personal dosimetry (using a monitor worn over 24 hours) on selected subjects to develop methods for comparing and combining other EMF measurements. Once all of the data have been collected, Boice said that an exposure
176
matrix will be developed. 'This matrix will estimate the exposure of EMFs for each year of life in both the children who developed ALL and their matched controls," he explained. "Such a matrix will provide one of the first credible views of the levels of lifetime EMF exposure experienced by children, both with and without leukemia," said Linet. "From those numbers, we should get a pretty good handle on whether EMF exposure is a factor in ALL development." Robison feels that "getting that handle" is critical to the overall success of the CCSG's ALL protocol. "We probably won't see many other attempts of this magnitude [to address the causes of childhood leukemia], so it's important to utilize the available resources now to answer questions about possible contributing factors," he said. "Our collaboration with NCI is a most effective way for finding the answers where EMFs are concerned," he added. —By Michael E. Newman
Perspective: Cancer Research in the 1980s Between 1980 and 1990, cancer research progress ranged from basic biology, to treatment, to an evolving public understanding of how lifestyle affects cancer risk. What produced these changes? A variety of events during the 1980s combined to revise scientific and public perceptions about cancer.
Breast Cancer One of the clearest examples was breast cancer, where treatment progress during the 1970s extended into the 1980s. During this 20-year period, the Halsted radical mastectomy gave way to lesser surgery. In 1985, a major clinical study of surgery options found that removing just the tumor and a safety margin of surrounding tissue, followed by radiation, was as effective
The traditional radical mastectomy devised in 1894 by Dr. William Halsted, right, of Johns Hopkins, has virtually faded from the breast cancer treatment picture in the 1980s.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on July 24, 2015
work," said Zdenek Hrubec, Ph.D., coproject officer for the EMF study. Finally, the study also benefits from being part of CCSG's large-scale protocol to identify as many of ALL's causes as possible. "Our results will be analyzed with regard to confounding factors and clinical parameters not readily available in standalone EMF studies," said John Boice, Jr., ScD., chief of NCI's Radiation Epidemiology Branch. Leslie Robison, Ph.D., epidemiologist at the University of Minnesota Health Sciences Center and principal investigator of the ALL protocol, said that NCI's EMF data will be incorporated and compared with research on other potential causal factors. "These include the extent of prenatal x rays, childhood and maternal diseases, maternal drug use, maternal smoking, parental occupations, household chemical exposures, and family genetic histories," he said.
Hews News
Another Consensus By 1985, another NIH Consensus Development Conference found adjuvant chemotherapy and hormonal therapy to be effective for many breast cancer patients. Although recognizing the absence of an optimal protocol, the panel recommended chemotherapy for all node-positive, premenopausal patients. For postmenopausal women with positive nodes and positive hormone receptors, the panel recommended tamoxifen therapy. Adjuvant therapy should be considered, the panel stated, only for nodenegative women at high risk of recurrence. Vol. 82, No. 3, February 7, 1990
Purified DNA, fluoresclng orange under UV light, is extracted and used for molecular biology studies. The purifled DNA, hi a cesium chloride gradient, binds to ethldium bromide dye, which absorbs UV light and makes the DNA fluoresce orange. This visualization of a single band of DNA aids in the isolation and extraction of the DNA for future molecular biology studies.
By 1989, results of several long-term studies demonstrated the benefit of adjuvant therapy even in women whose tumor was limited to the breast and had not spread to any lymph nodes. Because breast cancer recurs in about 30% of these patients, NCI recommended that physicians consider adjuvant therapy for breast cancer patients who fell into this category. However, this recommendation was controversial. The studies had not yet determined whether adjuvant therapy resulted in a survival advantage. A third consensus conference, scheduled for May 1990, will look at where the research stands now, in an effort to resolve remaining questions.
Colon Cancer Colon cancer provided another example of the development of adjuvant therapy. Results of an NCI-sponsored
clinical trial published in March 1984 failed to show any advantage, either in recurrence rates or survival, in stages B2, Cl, and C2 colon cancer patients given certain kinds of chemotherapy or biological therapy after surgery. This study set the standard for patient care throughout the decade. The Associated Press reported on the study by announcing in a headline, "Chemotherapy Doesn't Improve Colon Cancer Survival," and warned of the side effects and leukemia risk due to the chemotherapy used in the study. In September 1989, however, results of a large clinical trial showed that using the drugs 5-fluorouracil and levamisole substantially reduced the death rate in patients with stage Dukes' C colon cancer. The study showed a 31% increase in disease-free survival, and a 31% increase in overall survival at 5 years. Results of a large, confirmatory trial will be published soon in the New England Journal of Medicine.
Basic Research Major changes occurred during the decade in understanding the genetic and molecular basis for cancer. Genesplicing, the revolutionary technique that won Paul Berg, Ph.D., of Stanford University the Nobel Prize in 1980 and helped create the field of biotechnology, became routine. Copying the genes for splicing into bacteria is now done by machines. And, automated DNA sequencers relieved researchers of much of the drudgery of gene mapping by electrophoresis, until the 1980s a rigorous task. The new DNA technology enabled scientists to tackle the task of understanding the entire molecular pathway of an oncogene, a type of disfigured gene that may underlie the genetic abnormalities of cancer. When whole and healthy, these genes probably govern life's most basic NEWS
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on July 24, 2015
in the early stages of the disease as total mastectomy. Trials of adjuvant therapies, however, were the hallmark of treatment developments in the 1980s. In announcing publication in 1989 of some of the newest breast cancer clinical trial results, Samuel Broder, M.D., director of the National Cancer Institute, said, "As a result of research findings like these, adjuvant therapy is becoming an integral part of everyday medical care." However, until 1989, the recommendations for use of adjuvant therapy were limited by the lack of clinical research data. In 1980, a panel of physicians and scientists participating in a National Institutes of Health Consensus Development Conference on adjuvant therapy for breast cancer recommended that patients with positive nodes receive chemotherapy. Hormonal treatment, combined with chemotherapy, had not shown enough benefit in clinical trials for the panel to recommend its routine use. Chemotherapy was not advised for stage I, node-negative patients. And, although scientists were seeing a longer disease-free period in postmenopausal, node-positive patients, the research findings were too preliminary to recommend chemotherapy for this group.
177
News News
Focus on Function Scientists now know the function of at least two of the normal genes, called proto-oncogenes. One, named sis, was found in 1983 to be identical to the gene that codes for a protein to stimulate blood cell growth. Another, called c-mos, was found in 1989 to code for a protein that readies mammalian eggs for fertilization. Scientists also discovered during the 1980s the significance of so-called recessive oncogenes. These genes, also called tumor suppressor genes, do damage only when both cellular copies are mutated or lost. One such gene is responsible for a rare, inherited form of childhood cancer called retinoblastoma, by failing to control cell division in developing retinal cells. Oncogenes are even suspected of playing a role in cancer progression, or metastasis. As scientists learn more about the genes controlling cell division and growth, they are attempting to apply their knowledge to diagnosis and treatment. Oncogene profiles are being monitored in clinical trials to see if they can accurately predict the course of a patient's disease.
have received tumor-infiltrating lymphocytes that contain a gene transferred from bacteria. The goal of the study, led by Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute, is to monitor the cells with the foreign gene to examine the long-term distribution and survival of TIL in the body. Rosenberg's work made headlines on several occasions during the 1980s, beginning in 1984 when the first cancer patients received lymphocyte-activated killer cells and interleukin-2 therapy. Ten percent of patients with advanced melanoma and renal cell cancer, treated with IL-2-based therapies, experience a complete response.
Biologicals During the 1980s, there was an influx into clinical trials of other biological agents that trigger the body's own defenses to fight cancer. Beginning in 1980, NCI contracted for production of both naturally and genetically engineered interferon. Clinical trials began
Gene Therapy Another significant development of the 1980s was the first gene therapy trial. Thus far, five melanoma patients
178
Mammograms arc recommended for early detection of breast cancer.
in 1981 at several locations around the country. Also in 1981, NCI formally established its Biological Response Modifiers Program to identify and promote the study of new biological therapies to fight cancer. In addition to the interferons and interleukins, NCI now sponsors studies of monoclonal antibodies, differentiation and maturation factors, colony stimulating factors, and tumor necrosis factors, both alone and combined with other biologicals and drugs.
Lifestyle During the 1980s, diet emerged more strongly as a risk factor for cancer. In 1984, NCI took the lead in recommending that Americans eat a diet low in fat and high in fiber from whole grain breads, cereals, and fresh fruits and vegetables. Attitudes toward tobacco use also changed markedly in the past 10 years. A lower percentage of Americans were smoking, smoking was banned in many public places, and new laws were passed to limit smoking on domestic airline flights. (See following story.) A paper published last fall (/ Natl Cancer Inst, Oct 18,1989) documented the decline in lung cancer mortality in white males that followed their drop-off in smoking during the 1970s and 1980s. Finally, the 1980s saw increased appreciation for the importance of early detection of cancer. In 1989, the divergent recommendations of a variety of medical organizations were unified into the guideline that all women aged 40 to 49 have a mammogram every 1 to 2 years, and that upon reaching age 50 they have one annually. Early detection guidelines are now also in place for cancers of the skin, cervix, colon, testes, prostate, and oral cavity. —By Patricia A. Newman Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on July 24, 2015
processes, such as cellular reproduction. When damaged, these genes cause normal cells to become cancer cells. The importance of oncogenes was underscored in 1989 when two scientists, Michael Bishop, M.D., and Harold Varmus, M.D., of the University of California at San Francisco received the Nobel Prize for their work in discovering oncogenes in the mid1970s.
Study Parameters From September 1989 through December 1993, approximately 1,000 ALL cases and 1,000 controls (in six mid-Atlantic and midwestern states) will be evaluated. These will be approximately half of the population being studied in the CCSG protocol. Evaluation parameters include questioning parents about EMF exposures, such as use of electric blankets; diagramming configurations of neighborhood power lines and residential wiring; taking spot and 24-hour measurements of EMFs in areas frequented by the children (both within and outside homes and schools); and conducting personal dosimetry (using a monitor worn over 24 hours) on selected subjects to develop methods for comparing and combining other EMF measurements. Once all of the data have been collected, Boice said that an exposure
176
matrix will be developed. 'This matrix will estimate the exposure of EMFs for each year of life in both the children who developed ALL and their matched controls," he explained. "Such a matrix will provide one of the first credible views of the levels of lifetime EMF exposure experienced by children, both with and without leukemia," said Linet. "From those numbers, we should get a pretty good handle on whether EMF exposure is a factor in ALL development." Robison feels that "getting that handle" is critical to the overall success of the CCSG's ALL protocol. "We probably won't see many other attempts of this magnitude [to address the causes of childhood leukemia], so it's important to utilize the available resources now to answer questions about possible contributing factors," he said. "Our collaboration with NCI is a most effective way for finding the answers where EMFs are concerned," he added. —By Michael E. Newman
Perspective: Cancer Research in the 1980s Between 1980 and 1990, cancer research progress ranged from basic biology, to treatment, to an evolving public understanding of how lifestyle affects cancer risk. What produced these changes? A variety of events during the 1980s combined to revise scientific and public perceptions about cancer.
Breast Cancer One of the clearest examples was breast cancer, where treatment progress during the 1970s extended into the 1980s. During this 20-year period, the Halsted radical mastectomy gave way to lesser surgery. In 1985, a major clinical study of surgery options found that removing just the tumor and a safety margin of surrounding tissue, followed by radiation, was as effective
The traditional radical mastectomy devised in 1894 by Dr. William Halsted, right, of Johns Hopkins, has virtually faded from the breast cancer treatment picture in the 1980s.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on July 24, 2015
work," said Zdenek Hrubec, Ph.D., coproject officer for the EMF study. Finally, the study also benefits from being part of CCSG's large-scale protocol to identify as many of ALL's causes as possible. "Our results will be analyzed with regard to confounding factors and clinical parameters not readily available in standalone EMF studies," said John Boice, Jr., ScD., chief of NCI's Radiation Epidemiology Branch. Leslie Robison, Ph.D., epidemiologist at the University of Minnesota Health Sciences Center and principal investigator of the ALL protocol, said that NCI's EMF data will be incorporated and compared with research on other potential causal factors. "These include the extent of prenatal x rays, childhood and maternal diseases, maternal drug use, maternal smoking, parental occupations, household chemical exposures, and family genetic histories," he said.
Hews News
Another Consensus By 1985, another NIH Consensus Development Conference found adjuvant chemotherapy and hormonal therapy to be effective for many breast cancer patients. Although recognizing the absence of an optimal protocol, the panel recommended chemotherapy for all node-positive, premenopausal patients. For postmenopausal women with positive nodes and positive hormone receptors, the panel recommended tamoxifen therapy. Adjuvant therapy should be considered, the panel stated, only for nodenegative women at high risk of recurrence. Vol. 82, No. 3, February 7, 1990
Purified DNA, fluoresclng orange under UV light, is extracted and used for molecular biology studies. The purifled DNA, hi a cesium chloride gradient, binds to ethldium bromide dye, which absorbs UV light and makes the DNA fluoresce orange. This visualization of a single band of DNA aids in the isolation and extraction of the DNA for future molecular biology studies.
By 1989, results of several long-term studies demonstrated the benefit of adjuvant therapy even in women whose tumor was limited to the breast and had not spread to any lymph nodes. Because breast cancer recurs in about 30% of these patients, NCI recommended that physicians consider adjuvant therapy for breast cancer patients who fell into this category. However, this recommendation was controversial. The studies had not yet determined whether adjuvant therapy resulted in a survival advantage. A third consensus conference, scheduled for May 1990, will look at where the research stands now, in an effort to resolve remaining questions.
Colon Cancer Colon cancer provided another example of the development of adjuvant therapy. Results of an NCI-sponsored
clinical trial published in March 1984 failed to show any advantage, either in recurrence rates or survival, in stages B2, Cl, and C2 colon cancer patients given certain kinds of chemotherapy or biological therapy after surgery. This study set the standard for patient care throughout the decade. The Associated Press reported on the study by announcing in a headline, "Chemotherapy Doesn't Improve Colon Cancer Survival," and warned of the side effects and leukemia risk due to the chemotherapy used in the study. In September 1989, however, results of a large clinical trial showed that using the drugs 5-fluorouracil and levamisole substantially reduced the death rate in patients with stage Dukes' C colon cancer. The study showed a 31% increase in disease-free survival, and a 31% increase in overall survival at 5 years. Results of a large, confirmatory trial will be published soon in the New England Journal of Medicine.
Basic Research Major changes occurred during the decade in understanding the genetic and molecular basis for cancer. Genesplicing, the revolutionary technique that won Paul Berg, Ph.D., of Stanford University the Nobel Prize in 1980 and helped create the field of biotechnology, became routine. Copying the genes for splicing into bacteria is now done by machines. And, automated DNA sequencers relieved researchers of much of the drudgery of gene mapping by electrophoresis, until the 1980s a rigorous task. The new DNA technology enabled scientists to tackle the task of understanding the entire molecular pathway of an oncogene, a type of disfigured gene that may underlie the genetic abnormalities of cancer. When whole and healthy, these genes probably govern life's most basic NEWS
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on July 24, 2015
in the early stages of the disease as total mastectomy. Trials of adjuvant therapies, however, were the hallmark of treatment developments in the 1980s. In announcing publication in 1989 of some of the newest breast cancer clinical trial results, Samuel Broder, M.D., director of the National Cancer Institute, said, "As a result of research findings like these, adjuvant therapy is becoming an integral part of everyday medical care." However, until 1989, the recommendations for use of adjuvant therapy were limited by the lack of clinical research data. In 1980, a panel of physicians and scientists participating in a National Institutes of Health Consensus Development Conference on adjuvant therapy for breast cancer recommended that patients with positive nodes receive chemotherapy. Hormonal treatment, combined with chemotherapy, had not shown enough benefit in clinical trials for the panel to recommend its routine use. Chemotherapy was not advised for stage I, node-negative patients. And, although scientists were seeing a longer disease-free period in postmenopausal, node-positive patients, the research findings were too preliminary to recommend chemotherapy for this group.
177
News News
Focus on Function Scientists now know the function of at least two of the normal genes, called proto-oncogenes. One, named sis, was found in 1983 to be identical to the gene that codes for a protein to stimulate blood cell growth. Another, called c-mos, was found in 1989 to code for a protein that readies mammalian eggs for fertilization. Scientists also discovered during the 1980s the significance of so-called recessive oncogenes. These genes, also called tumor suppressor genes, do damage only when both cellular copies are mutated or lost. One such gene is responsible for a rare, inherited form of childhood cancer called retinoblastoma, by failing to control cell division in developing retinal cells. Oncogenes are even suspected of playing a role in cancer progression, or metastasis. As scientists learn more about the genes controlling cell division and growth, they are attempting to apply their knowledge to diagnosis and treatment. Oncogene profiles are being monitored in clinical trials to see if they can accurately predict the course of a patient's disease.
have received tumor-infiltrating lymphocytes that contain a gene transferred from bacteria. The goal of the study, led by Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute, is to monitor the cells with the foreign gene to examine the long-term distribution and survival of TIL in the body. Rosenberg's work made headlines on several occasions during the 1980s, beginning in 1984 when the first cancer patients received lymphocyte-activated killer cells and interleukin-2 therapy. Ten percent of patients with advanced melanoma and renal cell cancer, treated with IL-2-based therapies, experience a complete response.
Biologicals During the 1980s, there was an influx into clinical trials of other biological agents that trigger the body's own defenses to fight cancer. Beginning in 1980, NCI contracted for production of both naturally and genetically engineered interferon. Clinical trials began
Gene Therapy Another significant development of the 1980s was the first gene therapy trial. Thus far, five melanoma patients
178
Mammograms arc recommended for early detection of breast cancer.
in 1981 at several locations around the country. Also in 1981, NCI formally established its Biological Response Modifiers Program to identify and promote the study of new biological therapies to fight cancer. In addition to the interferons and interleukins, NCI now sponsors studies of monoclonal antibodies, differentiation and maturation factors, colony stimulating factors, and tumor necrosis factors, both alone and combined with other biologicals and drugs.
Lifestyle During the 1980s, diet emerged more strongly as a risk factor for cancer. In 1984, NCI took the lead in recommending that Americans eat a diet low in fat and high in fiber from whole grain breads, cereals, and fresh fruits and vegetables. Attitudes toward tobacco use also changed markedly in the past 10 years. A lower percentage of Americans were smoking, smoking was banned in many public places, and new laws were passed to limit smoking on domestic airline flights. (See following story.) A paper published last fall (/ Natl Cancer Inst, Oct 18,1989) documented the decline in lung cancer mortality in white males that followed their drop-off in smoking during the 1970s and 1980s. Finally, the 1980s saw increased appreciation for the importance of early detection of cancer. In 1989, the divergent recommendations of a variety of medical organizations were unified into the guideline that all women aged 40 to 49 have a mammogram every 1 to 2 years, and that upon reaching age 50 they have one annually. Early detection guidelines are now also in place for cancers of the skin, cervix, colon, testes, prostate, and oral cavity. —By Patricia A. Newman Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Sussex on July 24, 2015
processes, such as cellular reproduction. When damaged, these genes cause normal cells to become cancer cells. The importance of oncogenes was underscored in 1989 when two scientists, Michael Bishop, M.D., and Harold Varmus, M.D., of the University of California at San Francisco received the Nobel Prize for their work in discovering oncogenes in the mid1970s.
