MEDICAL MONDAYS: News Notes
Monday, June 18, 2012
TOPIC: Advances in Cancer Research & Treatment
Nancy Peacock, MD: oncologist
GREATER NASHVILLE RESIDENTS ASKED TO CONTRIBUTE TO HISTORIC CANCER RESEARCH EFFORT
Residents of Greater Nashville and Middle Tennessee have an unprecedented opportunity to participate in a historic study that has the potential to change the face of cancer for future generations.
Men and women between the ages of 30 and 65 who have never been diagnosed with cancer are needed to participate in the American Cancer Society's Cancer Prevention Study-3 (CPS-3). CPS-3 will enroll a diverse population of at least 300,000 adults across the United States and Puerto Rico. The study will help researchers better understand the lifestyle, environmental, and genetic factors that cause or prevent cancer.
Participation is easy and enrollment is being brought to the hospitals of Saint Thomas Health, Middle Tennessee YMCAs and the Matthew Walker Comprehensive Health Clinic.
Enrollment begins the week of July 10 at any of these locations, but you're encouraged to make your appointment now:
SAINT THOMAS HOSPITAL | Tuesday, July 10 | 7a - 1p and 4 - 8p
BAPTIST HOSPITAL | Thursday, July 12 | 7a – 1p and 4 - 8p
MIDDLE TENNESSEE MEDICAL CENTER | Tuesday, July 10 | 7a – 1p and 4 - 8p
News Notes via New England Journal of Medicine
200 Years of Cancer Research | New England Journal of Medicine
Published June 7, 2012 | http://www.nejm.org/doi/full/10.1056/NEJMra1204479
In the 200 years since the New England Journal of Medicine was founded, cancer has gone from a black box to a blueprint. During the first century of the Journal's publication, medical practitioners could observe tumors, weigh them, and measure them but had few tools to examine the workings within the cancer cell.
But the lid of the black box was not seriously pried open until 1944, when a retired scientist at Rockefeller University, Oswald Avery, reported the results of his beautifully clear experiments with the pneumococcal bacillus, which showed that cellular information was transmitted not by proteins but by DNA. His work led directly to the important discovery of the structure of DNA by Watson and Crick in 1953.
Early investigators discovered that DNA is a very large molecule that was difficult to study in the laboratory. These discoveries gave birth to the molecular revolution and the biotechnology industry. They also paved the way for the sequencing of the genome.
This kind of science was expensive. The U.S. Congress partially addressed the problem by passing the National Cancer Act, which expanded the role of the National Cancer Institute (NCI), the first disease-oriented agency at the National Institutes of Health (NIH). The act, which was signed into law on December 23, 1971, by President Richard Nixon, created a new mandate for an NIH institute: "to support research and the application of the results of research to reduce the incidence, morbidity and mortality from cancer."
Although the enthusiasm in Congress for eradicating cancer was largely derived from excitement over a few clinical advances, about 85% of these new funds went to support basic research. At its peak in the early 1980s, the NCI accounted for 23% of the budget of the NIH, yet it supported 53% of the research in molecular biology in the United States. And the results have been explosive.
The discovery of genes that drive or suppress cellular growth and the complex regulation of signaling systems used by both normal cells and cancer cells to communicate with each other and their environment have brought the blueprint of cancer-cell machinery into bold relief. The association of specific abnormalities with specific cancers has allowed scientists to identify persons who are at increased risk for common cancers, such as breast and colon cancer.
Milestones in Cancer Treatment
Experiments that can be done in hours in the laboratory take months and years to replicate in the clinic, so clinical advances, though plentiful, develop slowly. The past two centuries four areas of focus include: cancer treatment, chemoprevention, viruses and cancer-vaccine development, and tobacco control.
In the treatment of cancer, surgery was the first tool available. In 1809, Ephraim McDowell removed an ovarian tumor without the use of anesthesia, the first abdominal surgery performed in the United States, and provided evidence that tumor masses could be cured by surgery.
The most profound influence on cancer surgery occurred in 1894, when William Halsted introduced radical mastectomy for breast cancer. It would be 74 years before the use of radical mastectomy and en bloc resection was questioned by another surgeon, Dr. Bernard Fisher. Fisher also showed that less radical surgery plus chemotherapy or radiation therapy accomplished the goal with much less morbidity. These studies revolutionized the treatment of breast cancer. Since then, most other surgical procedures have been tailored to the availability of other treatments, and cancer surgery has become more effective, with less morbidity. In the first half of the 20th century, however, surgery was the only option, and a minority of patients could be cured by surgical removal of their tumors alone.
The era of radiation treatment began in 1895, when Roentgen reported on his discovery of x-rays, and accelerated in 1898 with the discovery of radium by Pierre and Marie Curie. In 1928, it was shown that head and neck cancers could be cured by fractionated radiation treatments, a milestone in the field. Like surgery, radiation therapy has become more effective, with less morbidity, and can be used in combination with other treatments.
By the 1950s, it had become apparent that no matter how complete the resection or how good the radiation therapy or how high the dose delivered, cure rates after surgery, radiation therapy, or the two combined had flattened out. Only about a third of all cancers could be cured by the use of these two treatment approaches, alone or together.
It was Paul Ehrlich at the turn of the 20th century who first made a concerted effort to develop chemicals to cure cancer. He coined the word "chemotherapy."
Proof of cure by chemotherapy had a permissive effect on the use of drugs as an adjuvant to surgery and radiation therapy. Doctors started to be willing to consider using chemotherapy by the mid-1970s. By 1991, thanks to the availability of multiple effective chemotherapeutic agents and hormone treatments, improved diagnostic tools for early diagnosis, and intelligently designed clinical trials, the rate of death from breast cancer began to fall, a trend that has continued. Early diagnosis and lumpectomy coupled with systemic therapy have greatly reduced the morbidity associated with breast-cancer treatment, with good cosmetic effects. Such advances have fulfilled the mandate of the war on cancer "to support research . . . to reduce the incidence, morbidity and mortality from cancer."
The success of adjuvant treatment of breast cancer, in turn, had a permissive effect on the use of drugs in the postoperative treatment of other major cancers, such as colorectal cancer. As a consequence of early diagnosis, prevention, and adjuvant treatment, the rate of death from colorectal cancer has fallen by 40% during the past four decades.
Another paradigmatic change in cancer treatment occurred in 2006, showing the efficacy of a drug (imatinib) that targeted the unique molecular abnormality in chronic myeloid leukemia. This work provided proof of principle that treatments targeting specific molecular abnormalities that are unique to certain cancers could convert them into manageable chronic illnesses. Since then, chemotherapy has become targeted therapy, and the literature has been dominated by the search for drugs to inhibit unique molecular targets, with recent success in the treatment of some very difficult-to-treat tumors, such as melanoma and lung cancer.
Until recently, cancer treatment was a three-legged stool sitting on a base of surgery, radiation therapy, and chemotherapy. In the past 25 years, immunotherapy has been added as an important component of cancer treatment.
The subsequent development of immunomodulatory agents, the development of cell-transfer therapies, and the use of genetically engineered lymphocytes to treat cancer have provided additional evidence of the ability of immunotherapy to mediate cancer regression. With the increasing use of these agents, the cancer-treatment platform sits firmly on four legs.
No matter how easy cancer treatment may become, it is preferable to prevent cancer. But prevention has been an elusive goal. When the cause of cancer is known, its prevention becomes a problem in modifying human behavior. Nicotine is one of the most addicting substances known, and exposure to tobacco smoke is by far the best known and most frequent cause of cancer, causing an estimated 40% of all deaths from cancer. It was suggested as early as 1912 that smoking might be related to lung cancer, with the epidemiologic evidence becoming solid in the 1950s.
To date, the historic goal of creating a cancer vaccine has been realized only for cancers that are caused by viral infections. Even when the causal virus has been identified, the elapsed time from discovery to prevention has been long. The human papillomavirus was discovered in 1907, but it was not linked to cervical cancer until 1976, and a vaccine to prevent infection by the virus in young girls was not approved by the FDA until 2000. Hepatitis B virus was discovered in 1967 and was linked to liver cancer in 1974. In 1984, it was shown that both hepatitis B and liver cancer could be prevented by vaccination against hepatitis B. Since then, in some parts of the world, vaccination of newborns against the hepatitis B virus has become routine. Since it is estimated that 20% of all cancers are caused in some way by viruses, further development of vaccines holds much promise.
The use of chemicals to prevent cancer (chemoprevention) can be effective. Antiestrogens can prevent ductal carcinoma in situ and reduce the incidence of breast cancer, finasteride can prevent prostate cancer, and plain old aspirin can prevent colorectal cancer. However, this approach is not widely used because large numbers of otherwise normal persons would need to be exposed to potentially toxic materials in order to prevent some cancers.
Survival Now and in the Future
Soon after the development of successful treatments in the 1970s, disease-specific death rates began to fall dramatically for childhood leukemia and Hodgkin's disease. The incidence of these diseases was too low to affect overall rates of death from cancer. Overall rates began to decline soon after the introduction of better early diagnosis and preventive measures and effective adjuvant treatment of common cancers, such as cancer of the breast and colon. The 5-year relative survival rate for all cancers, which was 38% in the late 1960s, just before the passage of the National Cancer Act, is now 68%. Straight-line projections indicate that the survival rate will rise to 80% by 2015. Overall rates of death from cancer, which began to decline in 1990 in the United States, have decreased by 24% overall since then. Straight-line projections to the year 2015 indicate that the overall absolute reduction in cancer mortality will be about 38 percentage points.
However, these projections are almost certainly underestimates, since they are based on the assumption that there will be little change in the management of cancer between now and 2015. Most of the current declines are the result of the widespread implementation of old technology for diagnosis, prevention, and treatment, stimulated by funds provided by the war on cancer. However, the biggest payoff from that investment — the clinical application of the fruits of the extraordinary molecular revolution initiated by the National Cancer Act — is yet to come and cannot be measured with the use of current statistics.
The sequencing of the human genome in 2000 has had a profound effect on all of medicine. The cost of sequencing is reminiscent of Moore's law, with the cost halving every 2 years. It is not difficult to foresee a time when a person's individual genome can be sequenced for as little as $100, putting genetic studies in the realm of a routine laboratory test. Starter companies with this aim already exist.
Second- and third-generation deep sequencing is revealing the complexity of the cancer blueprint and no doubt will reveal networks not yet imagined. Nonetheless, we are clearly facing a future in which patients with cancer or those at increased risk will have their genome sequenced as a matter of routine, with comparisons between the premalignant tissue and the malignant tissue. Detected abnormalities will become targets of relatively simple drug therapies, and if the effects mirror what we have seen in recent years with targeted therapy, the ability to prevent or treat cancers in the future will be impressive. The economic and social consequences of converting cancer into a curable or chronic disease will be both gratifying and daunting. This overview of 200 years of the cancer field provides support for the principle of the value of patience and investment in research.