Boring Good Health
Medical science is not focused on prevention of cancer because it is almost impossible to get research grants for it. Unlike a tumor to cut out, you can’t see prevention. It earns no fat fees, sells no drugs, confers no status, hones no surgical skills, plumps no resumes, buys no publicity, provides no immediate gratification at all. No researcher or agency can convincingly claim the credit for prevention. Few, therefore, are motivated to try.
– Michael Colgan, PhD. You Can Prevent Cancer, Apple Tree Publishing 2007.
Related Posts:
More Borrowed Words here.
Tags: breast cancer, cancer
Andrea
Lucy* (10)
Bayla* (8)
Prevention is SO hard to sell in so many fields. Look at needle exchange). Saves on HIV and Hep-C infections, etc. etc. etc. But YOU'RE ENABLING DRUG USE BLAH BLAH! So you have to fight like hell.
The hard thing, I think (or at least ONE of the hard things) is that it's difficult to quantify lives saved, health-care dollars saved by someone NOT getting sick. Think of how much money your cancer treatments have cost. If you in some way could have prevented your cancer, that money doesn't sit in a pile of toonies and five-dollar bills saying “WOW, look at what we just saved!”
Frustrating.
Exactly.
According to Derek Sivers, “in China, some doctors are paid monthly when you are healthy.If you are sick, it's their fault, so you don't have to pay that month. It's their goal to get you healthy and keep you healthy so they can get paid.
That's the makings of a healthy society, eh?
Well said!!! I have often thought the same during several rough moments during my Mom's cancer journey. The sad reality is that there is a cancer INDUSTRY that profits from people getting cancer, rather than not getting cancer. (And it profits even more if the cancer recurs.) So as you said, unfortunately there is a strong DISincentive against preventive efforts/ research. Of course, we can hope that some scientists will persevere with preventive research for altruistic reasons, but as you said, it is difficult to get funding for preventive research. I saw from the “resources” list on your website that you are already aware of an important book regarding preventive strategies: “Anticancer: A New Way of Life” by Dr. David Servan-Schreiber. I will recommend another book, by the “Father of Integrative Oncology,” Dr. Keith Block, titled “Life Over Cancer.” He runs an integrative oncology center near Chicago, and he has 30 years of experience in improving patients' outcomes. And here is a copy of a brow-raising article from PREVENTION magazine. This one is a real eye-opener, because it says things that I had not heard before (regarding cancer clusters, etc). Excerpt: “An an increasingly alarmed army of international scientists have come to a controversial conclusion: The “electrosmog” that first began developing with the rollout of the electrical grid a century ago and now envelops every inhabitant of Earth is responsible for many of the diseases that impair–or kill–us.” The (surprising) recommendations are at the top, and the explanatory summary follows below that. I will try to include a copy of the accompanying “full investigative report” for you in a separate comment. (I will also including a link to the Prevention Magazine article online at the end:)
Prevention Magazine
11 Ways to Protect Yourself
Exposure to electromagnetic fields may seriously harm your health. Here are easy ways to minimize the damage.
1. Avoid wireless when possible
EMF in the radio range accumulates, so if possible, choose wired Internet instead of wireless, a wired home security system, and wired entertainment systems. If you do use WiFi, plug in only when needed, and disconnect during sleeping hours. Keep the router as far as possible from your desk and children’s rooms.
2. Choose an old-school landline phone
Cordless phones can emit just as much radiation as mobile phones, although only when you’re using them. Consider reinstalling corded (land-line) phones. Avoid very powerful digital enhanced cordless telecommunications (DECT) phones—the kind with a base station and satellite handsets.
3. Ban Bluetooth headsets
When on a cell phone, use the speakerphone or a wired earpiece (hollow cord types are preferable). Do not use a Bluetooth wireless headset; combined with the phone, it can exceed even the current inadequate safety limits.
Give text messaging a try, especially in place of short calls. It’s safer than holding the phone to your head. Do not allow children to use cordless or cell phones, except for emergencies.
4. Keep your laptop off your lap
Curling up on the couch with your laptop may be convenient, but EMF experts recommend against it. Many laptops produce a strong electromagnetic field, especially when you use one while it’s plugged into an outlet (that means the battery is charging close to where your hands are). You’re better off unplugging and using the laptop on battery power, then staying away from it while it recharges.
5. Don’t wear your phone like a beeper
A better place for your cell or BlackBerry is in your purse or briefcase, because electromagnetic field exposure diminishes rapidly beyond 3 feet. It’s okay to carry it on you if the device is in “flight” or “off-line” mode. If you must carry it while fully on, keep the keypad positioned toward your body, so that the battery pack faces outward.
Don't let your teenager sleep with a cell phone under his or her pillow.
Another safety tip: Switch which side of the head you use your phone on from call to call so you spread out exposure.
6. Think LCD over plasma
When it’s time to upgrade
your TV, choose an LCD (liquid crystal display) instead of plasma or the old CRT (cathode ray tube) models. LCDs emit much less radiation, and plasmas can give off transient pollution on your electrical wiring.
7. Pick safer lightbulbs
Avoid compact fluorescent bulbs, which emit dirty electricity. A CFL saves energy by turning itself on and off repeatedly, as many as 100,000 times per second. Use LED or incandescent bulbs instead. Do not install dimmer switches (rheostats) for the same reason.
8. Stay away from the circuit breaker
Main electrical and circuit breaker panels give off high EMF within 3 to 4 feet. Make sure your bed is safely distant, and keep in mind the panel may be on the floor above or below you or on the other side of a wall.
9. Skip your cell when the service is spotty
If you struggle to get a signal or tend to drop calls in a certain area (common in elevators, buses, cars, and other enclosed spaces), wait until the signal is stronger. When handling a weak signal, the phone increases power to a maximum, irradiating you and those around you.
10. Unplug what you’re not using
If your kitchen counter is cluttered with a coffeepot, slow cooker, food processor, or other convenient culinary appliances, keep them unplugged whenever you’re not currently using them. Same goes for alarm clocks, lamps, iPod chargers and other various devices around your home. Anything plugged into an electrical outlet—even a lamp—emits an EMF; if unplugged, it will not.
11. Get your home tested
If you suspect that your home has high-EMF fields, check if your utility company conducts a room-by-room survey. It’s usually free. Hot spots can be completely shielded with special coverings. If you discover high levels of dirty electricity, consider installing filters (capacitors) that plug into electrical outlets ($35 at lessemf.com).
Is Electricity Making You Sick? Read our full report on the dangers—and solutions
Why Are Electromagnetic Fields Dangerous?
Several developments have highlighted the growing hazards of EMF pollution—and the crucial need to address them.
A report that cited more than 2,000 studies found that chronic exposure to even low-level radiation (like that from cell phones) can cause a variety of cancers
, impair immunity, and contribute to Alzheimer’s disease and dementia, heart disease, and many other ailments. One likely way: EMFs open the blood-brain barrier, causing blood vessels to leak fluid into the brain and damage neurons.
What’s more, a less–well known kind of EMF, known as “dirty” or transient electricity, may play an even more damaging role. Transients are largely by-products of modern energy-efficient electronics and appliances—from computers, refrigerators, and plasma TVs to compact fluorescent lightbulbs and dimmer switches—which tamp down the electricity they use. This manipulation of current creates a wildly fluctuating and potentially dangerous electromagnetic field that essentially charges up the electrons in every cell of your body. Some research suggests that by overlapping the body’s signaling mechanisms, transients may interfere with the secretion of insulin, drown out the call and response of the immune system, and cause other physical havoc.
Luckily, there are some things you can do to protect your health. Environmental consultant Cindy Sage recommends these simple steps to limit your exposure to electromagnetic fields from all sources.
For more information on the dangers of electromagnetic fields, read our full investigative report here. [See copy in next comment that Jana posts.]
Here is a copy of the “full investigative report” (with a link to the online article at the end):
Prevention Magazine
Electromagnetic Fields and Your Health
Is Dirty Electricity Making You Sick?
Too many electromagnetic fields surrounding us–from cell phones, wifi, and commonplace modern technology–may be seriously harming our health. Here's how to minimize your exposure.
By Michael Segell
The California Cluster
IN 1990, the city of La Quinta, CA, proudly opened the doors of its sparkling new middle school. Gayle Cohen, then a sixth-grade teacher, recalls the sense of excitement everyone felt: “We had been in temporary facilities for 2 years, and the change was exhilarating.” But the glow soon dimmed. One teacher developed vague symptoms– weakness, dizziness–and didn't return after the Christmas break. A couple of years later, another developed cancer and died; the teacher who took over his classroom was later diagnosed with throat cancer. More instructors continued to fall ill, and then, in 2003, on her 50th birthday, Cohen received her own bad news: breast cancer. “That's when I sat down with another teacher, and we remarked on all the cancers we'd seen,” she says. “We immediately thought of a dozen colleagues who had either gotten sick or passed away.” By 2005, 16 staffers among the 137 who'd worked at the new school had been diagnosed with 18 cancers, a ratio nearly 3 times the expected number. Nor were the children spared: About a dozen cancers have been detected so far among former students. A couple of them have died.
Prior to undergoing her first chemotherapy treatment, Cohen approached the school principal, who eventually went to district officials for an investigation. A local newspaper article about the possible disease cluster caught the attention of Sam Milham, MD, a widely traveled epidemiologist who has investigated hundreds of environmental and occupational illnesses and published dozens of peer-reviewed papers on his findings. For the past 30 years, he has trained much of his focus on the potential hazards of electromagnetic fields (EMFs)–the radiation that surrounds all electrical appliances and devices, power lines, and home wiring and is emitted by communications devices, including cell phones and radio, TV, and WiFi transmitters. His work has led him, along with an increasingly alarmed army of international scientists, to a controversial conclusion: The “electrosmog” that first began developing with the rollout of the electrical grid a century ago and now envelops every inhabitant of Earth is responsible for many of the diseases that impair–or kill–us.
See 11 Ways to Protect Yourself from Dirty Electricity
Milham was especially interested in measuring the ambient levels of a particular kind of EMF, a relatively new suspected carcinogen known as high-frequency voltage transients, or “dirty electricity.” Transients are largely by-products of modern energy-efficient electronics and appliances–from computers, refrigerators, and plasma TVs to compact fluorescent lightbulbs and dimmer switches–which tamp down the electricity they use. This manipulation of current creates a wildly fluctuating and potentially dangerous electromagnetic field that not only radiates into the immediate environment but also can back up along home or office wiring all the way to the utility, infecting every energy customer in between. With Cohen's help, Milham entered the school after hours one day to take readings. Astonishingly, in some classrooms he found the surges of transient pollution exceeded his meter's ability to gauge them. His preliminary findings prompted the teachers to file a complaint with the Occupational Safety and Health Administration, which in turn ordered a full investigation by the California Department of Health Care Services.
The final analysis, reported by Milham and his colleague, L. Lloyd Morgan, in 2008 in the American Journal of Industrial Medicine: Cumulative exposure to transients in the school increased the likelihood a teacher would develop cancer by 64%. A single year of working in the building raised risk by 21%. The teachers' chances of developing melanoma, thyroid cancer, and uterine cancer were particularly high, as great as 13 times the average. Although not included in the tabulations, the risks for young students were probably even greater.
“In the decades-long debate about whether EMFs are harmful,” says Milham, “it looks like transients could be the smoking gun.”
The Case against EMFs
Cancer and Electricity–could a disease whose cause has long eluded scientists be linked to perhaps the greatest practical discovery of the modern era? For 50 years, researchers who have tried to tie one to the other have been routinely dismissed by a variety of skeptics, from congressional investigators to powerful interest groups–most prominently electric utilities, cell phone manufacturers, and WiFi providers, which have repeatedly cited their own data showing the linkage to be “weak and inconsistent.” Recently, however, in addition to the stunning new investigations into dirty electricity (which we'll return to), several developments have highlighted the growing hazards of EMF pollution–and the crucial need to address them.
The Evidence showing harm is overwhelming.
In 2007, the Bioinitiative Working Group, an international collaboration of prestigious scientists and public health policy experts from the United States, Sweden, Denmark, Austria, and China, released a 650-page report citing more than 2,000 studies (many very recent) that detail the toxic effects of EMFs from all sources. Chronic exposure to even low-level radiation (like that from cell phones), the scientists concluded, can cause a variety of cancers, impair immunity, and contribute to Alzheimer's disease and dementia, heart disease, and many other ailments. “We now have a critical mass of evidence, and it gets stronger every day,” says David Carpenter, MD, director of the Institute for Health and the Environment at the University at Albany and coauthor of the public-health chapters of the Bioinitiative report.
Fears about the hazards of cell phones seem justified.
“Every single study of brain tumors that looks at 10 or more years of use shows an increased risk of brain cancer,” says Cindy Sage, MA, coeditor of the report. A recent study from Sweden is particularly frightening, suggesting that if you started using a cell phone as a teen, you have a 5 times greater risk of brain cancer than those who started as an adult. The risk rises even more for people who use the phone on only one side of the head. While defenders of cell phone safety claim no scientist can explain why EMFs may be harmful in humans, a body of reliable and consistent animal research shows that electromagnetic fields, equal to those generated by mobile phones, open the blood-brain barrier, causing blood vessels to leak fluid into the brain and damage neurons. Ironically, that research (by renowned Swedish neuro-oncologist Leif G. Salford, MD, PhD) began with the goal of finding a way to deliver chemotherapy to brain tumors.
See the worst time to use a cell phone
Other countries are revising exposure standards.
Members of the European Union, which has led the way on EMF investigations, are moving quickly to protect their citizens, particularly children and pregnant women. In the past 2 years alone, France, Germany, and England have dismantled wireless networks in schools and public libraries, and other countries are pressing to follow suit. Israel has banned the placement of cellular antennae on residences, and Russian officials have advised against cell phone use for children under 18.
Electrical hypersensitivity (EHS) is becoming more widespread.
Symptoms of EHS, a recently identified condition, include fatigue, facial irritation (resembling rosacea), tinnitus, dizziness, and digestive disturbances, which occur after exposure to visual display units, mobile phones, WiFi equipment, and commonplace appliances. Experts say up to 3% of all people are clinically hypersensitive, as many as one-third of us to a lesser degree.
Electrical pollution is increasing dramatically.
“For the first time in our evolutionary history, we have generated an entire secondary, virtual, densely complex environment–an electromagnetic soup–that essentially overlaps the human nervous system,” says Michael Persinger, PhD, a neuroscientist at Laurentian University who has studied the effects of EMFs on cancer cells. And it appears that, more than a century after Thomas Edison switched on his first lightbulb, the health consequences of that continual overlap are just now beginning to be documented.
A History of Harmful Effects
Until Edison's harnessing of electricity, humans' only sources of EMF exposure were the earth's static magnetic field (which causes a compass needle to point north) and cosmic rays from the sun and outer space; over our long evolution, we've adapted to solar EMFs by developing protective pigment. “But we have no protection against other EMF frequencies,” says Andrew Marino, PhD, JD, a pioneer in bioelectromagnetics who has done extensive EMF research and a professor in the department of orthopedic surgery at the Louisiana State Health Sciences Center. “How quickly can we adapt our biology to these new exposures? It's the most important environmental health question–and problem–of the 21st century.”
Research into the hazards of EMFs has been extensive, controversial–and, at least at the outset, animated by political intrigue. A sampling:
* The Russians first noticed during World War II that radar operators (radar operates using radio frequency waves) often came down with symptoms we now attribute to electrical hypersensitivity syndrome. In the 1960s, during the height of the Cold War, they secretly bombarded the US embassy in Moscow with microwave radiation (a higher-frequency RF used to transmit wireless signals), sickening American employees. Radio wave sickness– also called microwave sickness– is now a commonly accepted diagnosis.
* When television (also radio wave) was introduced in Australia in 1956, researchers there documented a rapid increase in cancers among people who lived near transmission towers.
* In the 1970s, Nancy Wertheimer, PhD, a Denver epidemiologist (since deceased), detected a spike in childhood leukemia (a rare disease) among kids who lived near electric power lines, prompting a rash of studies that arrived at similar conclusions.
* In the 1980s, investigators concluded that office workers with high exposure to EMFs from electronics had higher incidences of melanoma–a disease most often associated with sun exposure– than outdoor workers.
* In 1998, researchers with the National Cancer Institute reported that childhood leukemia risks were “significantly elevated” in children whose mothers used electric blankets during pregnancy and in children who used hair dryers, video machines in arcades, and video games connected to TVs.
* Over the past few years, investigators have examined cancer clusters on Cape Cod, which has a huge US Air Force radar array called PAVE PAWS, and Nantucket, home to a powerful Loran- Cantenna. Counties in both areas have the highest incidences of all cancers in the entire state of Massachusetts.
* More recently, the new findings on transients–particularly those crawling along utility wiring–are causing some scientists to rethink that part of the EMF debate pertaining to the hazards of power lines. Could they have been focusing on the wrong part of the EMF spectrum?
Transients: The Post- Modern Carcinogen
Some earlier, notable–albeit aborted–research suggests this may be the case. In 1988, Hydro-Quebec, a Canadian electric utility, contracted researchers from McGill University to study the health effects of power line EMFs on its employees. Gilles Theriault, MD, DrPH, who led the research and was chair of the department of occupational health at the university, decided to expand his focus to include high-frequency transients and found, even after controlling for smoking, that workers exposed to them had up to a 15-fold risk of developing lung cancer. After the results were published in the American Journal of Epidemiology, the utility decided to put an end to the study.
That research commenced at a time when energy-efficient devices–the major generators of transients–were beginning to saturate North American homes and clutter up power lines. A telltale sign of an energy-efficient device is the ballast, or transformer, that you see near the end of a power cord on a laptop computer, printer, or cell phone charger (although not all devices have them). When plugged in, it's warm to the touch, an indication that it's tamping down current and throwing off transient pollution. Two of the worst creators of transient radiation: light dimmer switches and compact fluorescent lightbulbs (CFLs). Transients are created when current is repeatedly interrupted. A CFL, for instance, saves energy by turning itself on and off repeatedly, as many as 100,000 times per second.
So how does the human body respond to this pulsing radiation? “Think of a magnet,” explains Dave Stetzer, an electrical engineer and power supply expert in Blair, WI. “Opposite charges attract, and like charges repel. When a transient is going positive, the negatively charged electrons in your body move toward that positive charge. When the transient flips to negative, the body's electrons are pushed back. Remember, these positive-negative shifts are occurring many thousands of times per second, so the electrons in your body are oscillating to that tune. Your body becomes charged up because you're basically coupled to the transient's electric field.”
Keep in mind that all the cells in your body, whether islets in the pancreas awaiting a signal to manufacture insulin or white blood cells speeding to the site of an injury, use electricity–or “electron change”–to communicate with each other. By overlapping the body's signaling mechanisms, could transients interfere with the secretion of insulin, drown out the call-and-response of the immune system, and cause other physical havoc?
See how light bulbs can make you sick
Some preliminary research implies the answer is yes. Over the past 3 years, Magda Havas, PhD, a researcher in the department of environmental and resource studies at Trent University in Ontario, has published several studies that suggest exposure to transients may elevate blood sugar levels among people with diabetes and prediabetes and that people with multiple sclerosis improve their balance and have fewer tremors after just a few days in a transient- free environment. Her work also shows that after schools installed filters to clean up transients, two-thirds of teachers reported improvement in symptoms that had been plaguing them, including headache, dry eye, facial flushing, asthma, skin irritation, and depression.
Transients are particularly insidious because they accumulate and strengthen, their frequency reaching into the dangerous RF range. Because they travel along home and utility wiring, your neighbor's energy choices will affect the electrical pollution in your house. In other words, a CFL illuminating a porch down the block can send nasty transients into your bedroom.
Something else is sending transients into your home: the earth. From your high school science texts, you know that electricity must travel along a complete circuit, always returning to its source (the utility) along a neutral wire. In the early 1990s, says Stetzer, as transients began overloading utility wiring, public service commissions in many states told utilities to drive neutral rods into the ground on every existing pole and every new one they erected. “Today, more than 70% of all current going out on the wires returns to substations via the earth,” says Stetzer–encountering along the way all sorts of subterranean conductors, such as water, sewer, and natural-gas pipes, that ferry even more electrical pollution into your home.
A Pragmatic Proposal
Of course, these small studies–from Milham, Hydro-Quebec, and Havas– hardly constitute a blanket indictment of transients. “We're still early in this part of the EMF story,” says Carpenter. Does that mean as evidence of their harm accumulates, officials will raise a red flag? Not likely, if past EMF debates are any indication. Power companies have successfully beaten back attempts to modify exposure standards, and the cell phone industry, which has funded at least 87% of the research on the subject, has effectively resisted regulation. One good reason has had to do with latency–how long it takes to develop a particular cancer, often 25 years or more. Cell phones have been around only about that long.
But does that mean we avoid any discussion of their possible dangers? Again, if the past is a guide, the answer appears to be “probably.” American scientists worried about the hazards of smoking, the DES (diethylstilbestrol) pill (given to pregnant women, it caused birth defects), asbestos, PCBs (polychlorinated biphenyls)–the list is lengthy–but officially warned about exposure only after they could say with absolute certainty that these things were harmful. As for protecting ourselves from toxic radiation, we have a lax–and laughable–history. In the 1920s, just a few years after medical imaging devices were invented, physicians were known to entertain their guests by x-raying them at garden parties. In the 1930s, scientists often kept radium in open trays on their desks. Shoe stores used x-ray machines in the 1940s to properly fit children's feet, and radioactive wristwatches with glowing hour hands were popular in the 1950s.
All of which means that, absent prudent safety standards from both public officials and manufacturers (adding a protective filter would add 5 cents to the cost of making a CFL and $5 to the cost of a laptop), you'll have to protect yourself from EMFs. Here's a reasonable proposition: Practice what is known in Europe as the precautionary principle, which is pretty much what it sounds like. Don't expose yourself unnecessarily to EMF hazards. Don't buy a home next to a WiFi tower. Get a corded telephone instead of a cordless one. Don't let your teenager sleep with a cell phone under her pillow. Don't use your laptop computer in your lap. Treat your EMF-emitting devices with the same cautious respect you do other invaluable modern devices, like your car, which is also dangerous–and can kill. You don't drive in an unnecessarily risky fashion–at high speed or while talking on a cell phone (right?).
The sad truth is that until we have more epidemiologic evidence–whether from disease clusters like the ones at La Quinta and on Cape Cod or from long-term analyses of the health of the world's 4-billion-and-growing cell phone users–we won't know definitively whether electrical pollution is harming us. And even then, we are unlikely to know why or how. “In this country, our research dollars are spent on finding ways to treat disease, not on what causes it–which is to say, how we can prevent it,” says Marino. “And that's a tragedy.”
But that's also another story.
The Opposing View: “No need for regulation”
In 1993, the National Institutes of health and Department of Energy began an extensive review of all studies on the possible health effects of electromagnetic fields. six years later they completed their project, called the Electric and Magnetic Fields research and public Information Dissemination (EMF RAPID) program, and reported their findings to Congress: scientific evidence of human health risk from EMF exposure is “weak,” they concluded.
While acknowledging a link between both childhood and adult leukemias and EMFs, the researchers' laboratory studies with cells and animals failed to identify a mechanism– that is, how EMFs might cause cancer. (read the EMF RAPID report at prevention.com/links)
To longtime EMF investigators such as David Carpenter, MD, the NIH dismissal of EMF hazards was patently absurd then and even more so now, given the spate of new findings. “We don't know the mechanism for most carcinogens,” he says. “there's this idea that anything that causes cancer must directly damage DNA, which is nonsense because most carcinogens don't directly damage DNA. and physicists are adamant that the energy in everyday EMF exposure is so low, it couldn't possibly do anything to biological systems. It's like saying the Earth is flat because you can't see over the edge.”
In fact, biological impacts of EMFs–therapeutic ones–are well known. Low-level frequencies are commonly used to promote healing of wounds and bone fractures, and experimental studies show positive effects of pulsed EMFs in treating pain and depression. recently, Michael persinger, PhD, a cognitive neuroscientist at Laurentian University, found that pulsed magnetic fields also halted the growth of melanoma cells in mice.
In a neat twist of logic, many scientists believe that the more we document beneficial effects of EMFs, the better we'll understand their hazards. “If EMF at low intensities can heal,” says environmental consultant Cindy sage, “then when we are constantly and randomly exposed to it from multiple sources, it may also be harmful, like any medicine used indiscriminately.”
What was wrong with the La Quinta School?
According to epidemiologist Sam Milham, MD, the middle school was rife with the usual suspects– fluorescent lighting, electronic devices–whose toxic effects were exacerbated by an electrical supply overloaded with high-voltage transients.
Substandard wiring in the new school also undoubtedly played a role; officials have since added protective shielding to the electrical room. Milham also measured transient pollution along the transmission lines that fed power to the school. “I found it all the way from the substation to the school–more than a mile,” Milham says. “There are three other buildings along the route that also serve children. I've reported it to the FCC and the utility, but they ignore the problem.”
How electrical pollution harms
Here, a partial spectrum of the electromagnetic fields that surround us, from strong (waves of extremely high frequency and short length) to weak (waves of extremely low frequency and long length). In each category, you'll find sources that generate the EMF, and associated health risks from overexposure.
X-Ray
[medical imaging devices]
Used to diagnose illness RISK
Damages tissue and organs by breaking bonds
VISIBLE LIGHT
[SUN]
The only visible EMF RISK
Ultraviolet light can burn skin and cause cancer
MICROWAVE (a higher frequency RF)
[CELL AND CORDLESS PHONES AND TOWERS]
Can heat tissues and penetrate blood-brain barrier RISK
Increased risk of brain cancer, dementia, and heart disease
RADIO(RF)
[RADIO AND TELEVISION SIGNALS]
Can disrupt body's cellular interactions RISK
“Radio sickness” and electrical hypersensitivity syndrome
EXTREMELY LOW FREQUENCY (ELF)
[POWER LINES]
Can cause weak electric currents to flow through the body RISK
Exposure is associated with childhood leukemia
See 11 Ways to Protect Yourself from Dirty Electricity
* Why Are Electromagnetic Fields Dangerous?
* 1. Avoid wireless when possible
* 2. Pick safer lightbulbs
* 3. Stay away from the circuit breaker
* 4. Choose an old-school land-line phone
* 5. Ban Bluetooth headsets
* 6. Skip your cell when the service is spotty
* 7. Don't wear your phone like a beeper
* 8. Keep your laptop off your lap
* 9. Unplug what you’re not using
* 10. Think LCD over plasma
* 11. Get your home tested
Copyright 2009, Prevention
http://www.prevention.com/health/health/healthy...
I received an email today, updating me on the latest issue of an oncology journal, and I noticed that the title of the lead article applies to PRE-menopausal patients, and I recall that you wrote that you have to decide which hormonal therapy to choose, so cc FYI. The main article is followed by two responses by other doctors:
Seven Considerations for Adjuvant Hormonal Therapy in Premenopausal Breast Cancer Patients
Seven areas of provocative data that should inform approaches to adjuvant therapy
http://www.cancernetwork.com/display/article/10...
ONCOLOGY. Vol. 24 No. 4
Focus on Breast Cancer
Adjuvant Hormonal Therapy in Premenopausal Women With Operable Breast Cancer: Not-So-Peripheral Perspectives
April 9, 2010
By Richard R. Love, MD
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio
The International Breast Cancer Research Foundation
Madison, Wisconsin
The Amader Gram Breast Care Program
ABSTRACT
Reviews of issues around adjuvant hormonal therapies for breast cancer in premenopausal women often focus on recent and current large clinical trials, and fail to address other subjects that are very germane to evidence-based and investigatory clinical practice. These topics include: (1) the descriptive epidemiology of breast cancer globally, (2) critical issues in tumor hormone receptor testing, (3) compelling data demonstrating that hormone receptor–positive breast cancer is a chronic disease, (4) data supportive of combined hormonal therapy with tamoxifen as the standard of care, and the limited justifications for awaiting the SOFT and TEXT trial results, (5) pharmacogenetic hypotheses with tamoxifen, (6) ethical issues in ovarian suppression vs ablative treatment, and (7) emerging data about the importance of primary tumor removal surgery itself and “surgical stress” in solid tumor management.
While optimal adjuvant hormonal therapies for premenopausal women with operable breast cancer have yet to be defined, discussions and reviews of the state of the art and “areas of confusion” often fail to consider developments that are germane to keeping evidence-based clinical practice truly up-to-date. The current communication is prompted by this perspective and a recent review and its commentaries.[2]
The late Jonathan Mann often said that the way we frame issues dictates how we approach them. Framing the challenges of getting to more effective adjuvant therapies for premenopausal women with hormone receptor–positive tumors within the context of our most recent and ongoing larger clinical trials only—which is what is usually done—is to ignore the richness and relevance of other provocative and emerging data that are directly applicable to clinical and investigative practice now. Here, I review such data in seven areas.
Descriptive Epidemiologic Data of Breast Cancer Globally
There are several reasons why we need to move away from perspectives and data based on North America only (or high-income countries only) in discussing breast cancer management. First, the cancer treatment and reading community is global, and we are increasingly called upon to be global citizens and speak to the needs of patients everywhere. In 2010, we will move to situations in which, worldwide, the majority of new annual cases of breast cancer will develop in Asian women (~800,000 of 1.5 million) and half will be in poor premenopausal women (~740,000 vs 44,000 premenopausal cases in the United States).[3,4]
Further, the fact that the overwhelming majority of our treatment data come from studies in women of northern European genetic background—with likely very specific tumor gene profiles and certainly different metabolic gene profiles—make the available data of uncertain relevance to this new majority of affected women who live in non-Western countries, as well as those women in Western countries of different genetic/ethnic backgrounds.[5-7] Finally, a common perception is that hormone receptor–positive breast cancer is less frequent in pre- than in postmenopausal women, but data from the Philippines, Vietnam, Taiwan, and China do not support this general conclusion.[8,9, and personal communications from Zhi Ming Shao, November 7, 2009; and from Ta Van To, May 2009]
In sum, our discussions about breast cancer management need to be more broadly sensitive and considerate of the global realities.
Tumor Hormonal Receptor Testing
While for some time there have been expressions of concern regarding quality control issues surrounding tumor hormonal receptor testing, the implications for practicing clinicians (and possible remedial actions) have not been obvious. With the upcoming publication of the American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) guidelines on hormonal receptor quality assurance, this situation should change. In the meantime, various data regarding one broad issue, which will be addressed in the guidelines, deserve all clinicians’ attention: choices of tissue specimens and their management prior to laboratory testing.
The relevant data include time to penetration and fixation of subsequently tested tumor tissues (optimally < 30 minutes), pH of fixative (optimally neutral, not acidic), and duration of fixation (optimally > 8–10 hours; less critically < 48 hours). Each of these factors influence determination of the presence and levels of hormonal receptor proteins.[10-12] Inattention to these parameters leads to more frequent findings of hormone receptor–negative tumors and lower levels of hormonal receptor proteins. When hormonal receptor determinations are done on core biopsy specimens, approximately 10% more tumors are found to be hormone receptor–positive, compared with when tests are done on subsequent mastectomy (and lumpectomy?) specimens.[13,14] The implications of these findings are clear:
• False-negative findings of hormonal receptor protein lead to depriving patients of important, recurrence-preventing hormonal therapies and in many circumstances choices of usually more toxic chemotherapy treatments.
• Clinicians need to be involved in the complete management sequence of tissue specimens obtained when hormonal receptor testing is part of the diagnostic panel.
• The diagnostic sequence for breast masses may, in some circumstances, need reconsideration. When the sequence includes a fine-needle aspiration biopsy, and hormonal receptor determinations are then done on subsequent mastectomy (as practiced in most of the world) or lumpectomy specimens, even greater attention to tissue management procedures is warranted. The case for core biopsy as the first diagnostic procedure, with this specimen used for hormonal receptor testing and with associated attention to optimal tissue management, deserves renewed consideration.
Hormone Receptor–Positive Breast Cancer as a Chronic Disease
Data from multiple sources are reinforcing what clinicians have been aware of for some time, but this awareness has not yet completely translated into thoughtful clinical practice and investigative medicine. For example:
• Measurable and steady rates of recurrence characterize meta-analysis populations of patients with hormone receptor–positive breast cancer (more so than those with hormone receptor–negative tumors) through 15 years after diagnosis.[15,16] There is a lag in return to higher rates of recurrence in the immediate years after hormonal therapies are stopped (eg, ~5 years).[15,17-19]
• In cases where hormonal therapies are given for longer than 5 years or started after 5 years from diagnosis, lower rates of recurrence occur in the 5- to 10-year postdiagnosis window.[17,20-22]
Current National Comprehensive Cancer Network (NCCN) guidelines suggest the use of adjuvant hormonal therapy with an aromatase inhibitor after 5 years (ie, for postmenopausal women, a status that all premenopausal women can achieve with chemotherapies, ovarian ablation, or continuing suppression therapies). However, there does not appear to be a consensus on this recommendation, at least as manifested in recommendations for therapies after 5 years in ongoing adjuvant studies. Clearly, there are many uncertainties about risks and benefits for subsets of patients, but the clear conclusion that hormone receptor–positive breast cancer is, for many (and perhaps the majority of patients), a chronic disease, must command more of our collective attention. Part of the reticence to more frequently and forthrightly consider this issue comes from the fact that patients find this to be an upsetting perspective, particularly because this is not how the disease has been framed in the past.
Combined Ovarian Suppression/Ablation and Tamoxifen Therapy as the Standard of Care
In 2003–2004, it may have been reasonable to assert that tamoxifen alone was the hormonal therapy standard of care for premenopausal women with hormone receptor–positive tumors. This was the conclusion of the Suppression of Ovarian Function Trial (SOFT) investigators, who assessed tamoxifen vs ovarian function suppression or ablation plus tamoxifen vs ovarian function suppression or ablation plus an aromatase inhibitor (exemestane [Aromasin]), giving each therapy for 5 years.[2] Many in the research community have continued to maintain that tamoxifen alone is the standard of care in this setting.
Austrian investigators reporting on the issue of ovarian suppression plus tamoxifen or an aromatase inhibitor (trial discussed below), whose study began accrual in 1999, apparently did not consider tamoxifen alone to be the standard of care a decade ago.[23] In 2009–2010, however, it is neither reasonable nor appropriate to assert (1) such equivalence of tamoxifen alone and combined therapy, and (2) to call for continued accrual to SOFT and the Tamoxifen/Exemestane Trial (TEXT), withholding judgment on the role of aromatase inhibitors in combined therapy until these trials report their results. The following findings support these contentions:
• In metastatic hormone receptor–positive disease, four individual trials and a meta-analysis have demonstrated improved outcomes with combined ovarian suppression plus tamoxifen therapy over either therapy alone.[24,25]
• In a large Intergroup trial, luteinizing hormone-releasing hormone (LHRH) alone after CAF chemotherapy (cyclophosphamide, doxorubicin [Adriamycin], fluorouracil [5-FU]), was inferior to LHRH plus tamoxifen (disease-free survival difference at 9 years = 8%; overall survival difference at 9 years = 3%).[26] In the metastatic setting, LHRH alone and tamoxifen alone appear to be equivalent therapies.[27]
• Meta-analysis of adjuvant data suggests that the combination of LHRH plus tamoxifen is better than tamoxifen alone.[28]
• In the Intergroup adjuvant trial, oophorectomy plus tamoxifen produced a disease-free survival rate of 90.3%, compared to 87.8% for tamoxifen alone.[29]
• In two European adjuvant trials, LHRH plus tamoxifen was superior to six cycles of IV CMF chemotherapy (cyclophosphamide, methotrexate, 5-FU), while LHRH alone was equivalent to six cycles of Bonadonna CMF chemotherapy.[30,31]
• In the author’s adjuvant trial of oophorectomy plus tamoxifen, this strategy resulted in a risk reduction of 0.58; in the meta-analysis of trials assessing adjuvant tamoxifen alone in premenopausal women, the risk reduction was 0.42.[15,19]
The consistency of the evidence—although mostly indirect—and the logic that two mechanisms of action are functioning with combined therapy, make the superiority of combined ovarian suppression plus tamoxifen therapy difficult to ignore.
The repeated counterargument is that direct evidence is needed, and the SOFT and TEXT trials will provide this. For the two hypotheses under investigation in those trials, this argument deserves careful scrutiny. However, compelling direct evidence is already available. Gnant et al presented survival data from the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial comparing LHRH plus anastrozole (Arimidex) and LHRH plus tamoxifen with or without zoledronic acid (Zometa) in premenopausal women with hormone receptor–positive breast cancer.[23] A 2×2 factorial design was used (1:1:1:1), with patients randomized to LHRH plus either anastrozole or tamoxifen, with or without zoledronic acid. The study enrolled 1,803 patients and was designed to test two primary hypotheses for the outcome of disease-free survival: (1) anastrozole against tamoxifen, and (2) zoledronic acid against no zoledronic acid.
While the addition of zoledronic acid exhibited a significant benefit in terms of disease-free survival, no difference in disease-free survival was found between the anastrozole and tamoxifen groups (P = .59, hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 0.78–1.53). A similar pattern was seen for recurrence-free survival (P = .53, HR = 1.11, 95% CI = 0.80–1.56), and a trend for overall survival was found in favor of tamoxifen (P = .07, HR=1.80, 95% CI: 0.95–3.38).[23] While a failure to reject the null hypothesis in a trial designed to test for superiority does not allow us to conclude the treatments are equivalent, there is no evidence from these data to support the superiority of anastrozole over tamoxifen in this population. However, given the size of this trial, the maturity of the data (median follow up of 48 months), and the pattern and trend of results, there is little justification for the position that the superiority of anastrozole compared with tamoxifen after ovarian ablation or with ovarian suppression alone remains an open question.
Thousands of further patients and years of follow-up will be required to demonstrate even a small effect, and these Gnant results would have to be considered in reaching conclusions about the “true” comparison results. Both the SOFT and TEXT trials also allow chemotherapy treatment. Looking to these trials for a different answer to the question of aromatase inhibitor or tamoxifen superiority in premenopausal women whose ovarian function is stopped, is neither appropriate nor realistic. While a definitive conclusion cannot be drawn from the Gnant study in terms of the survival benefits of anastrozole over tamoxifen in the premenopausal setting, a reasonable decision is to proceed as though the treatment results are similar.
Pharmacogenetic Hypotheses About Tamoxifen
The role of metabolic activation in tamoxifen activity was recognized in the 1970s, when the minor metabolite of tamoxifen, 4-hydroxytamoxifen, was shown to have 100-fold greater affinity than tamoxifen toward estrogen receptors and subsequently 30- to 100-fold greater potency than tamoxifen in suppressing estrogen-dependent cell proliferation.[32] However, the contribution of this metabolite to the overall clinical effect of tamoxifen has remained unclear because its plasma concentrations are relatively low compared with those of tamoxifen or some of its other metabolites.
Our knowledge of the link between tamoxifen metabolism and response expanded rapidly subsequent to the characterization of another active metabolite, N-desmethyl 4-hydroxy-tamoxifen (endoxifen), by Indiana University investigators 7 years ago.[33,34] A series of laboratory studies carried out to characterize its pharmacology have now established that endoxifen has equivalent potency to 4-hydroxytamoxifen in terms of binding affinity to estrogen receptors, suppression of estrogen-dependent proliferation of breast cancer cells, and modulation of estrogen-mediated global gene expression [35, and references listed therein].
In vitro, these investigators have shown that endoxifen is formed primarily via 4-hydroxylation of the primary tamoxifen metabolite, N-desmethyltamoxifen, by the CYP2D6 enzyme.[36] Consistent with these in vitro findings, the steady-state endoxifen plasma concentrations during tamoxifen treatment were substantially reduced in women who carry CYP2D6 genetic variants or coprescribed CYP2D6 inhibitors.[33,37,38] More importantly, the steady-state plasma concentrations of endoxifen that are achieved at 4 months after tamoxifen therapy[37] were on average 10-fold higher than those of 4-hydroxytamoxifen, with a large degree of interpatient variability (up to 100-fold greater endoxifen exposure relative to 4-hydroxytamoxifen in some patients).[33,37,38] Given that CYP2D6 is an important pathway in the formation of endoxifen and that this metabolite contributes importantly to the in vitro activity of tamoxifen, it is logical to suggest that endoxifen predicts outcome.
In these studies, the investigators noted some variability in the endoxifen plasma concentration, which remains unexplained even after correction for CYP2D6 genotype and medication history.[33,37,38] Endoxifen plasma concentrations are likely to be dependent not only on its formation by CYP2D6, but also on its clearance by phase II enzymes.
Recent in vitro data suggest that endoxifen is predominantly O-glucuronidated by the UDP-glucuronosyltransferase (UGT) 2B7 enzyme.[39] Accordingly, a common mis-sense SNP resulting in a His>Tyr amino acid change at residue 268 of the UGT2B7 enzyme was recently shown to be associated with altered glucuronidation activity against endoxifen, with the UGT2B7268Tyr variant isoform (encoded by the UGT2B7*2 allele) exhibiting significantly decreased activity.[40] Therefore, it is now hypothesized that differences in UGT2B7 and in combination with CYP2D6 contribute to tamoxifen response.
Two recent reviews and two editorials summarized the current status regarding CYP2D6 polymorphisms, metabolites, and clinical outcomes.[35,41-43] Approximately eight studies in Caucasian and Asian patients have suggested that CYP2D6 intermediate or poor metabolizer allelic status is associated with poorer outcomes in prevention, adjuvant, and metastatic settings, and three studies have suggested the reverse.[44-54] Both reviews note the absence of studies in which CYP2D6 genotype and endoxifen levels have been studied with clinical outcomes and call for validation studies, in particular noting, “Investigating a direct relationship of endoxifen plasma concentration with clinical outcome is imperative.”[41,42] Unlike circumstances in Caucasians, the most frequent CYP2D6 allele in Asians is CYP2D6*10.
In summary, the pharmacogenetics of tamoxifen are incompletely understood, and the primary hypothesis that has emerged—that concentrations of the endoxifen metabolite are related to clinical outcomes—needs to be evaluated in the context of a prospective clinical trial.
Ethical Issues in Ovarian Suppression vs Ablative Treatment
In metastatic hormone receptor–positive breast cancer, treatments with LHRH agonists and surgical oophorectomy are associated with similar outcomes.[55,56] The data on this adjuvant comparison in premenopausal women are too limited and indirect to reach a conclusion, but there is no reason to expect incomparability, except on the question of the duration of LHRH therapy.[15,28]
From the time of the first meta-analysis report suggesting that adjuvant ovarian ablation (by surgery or radiation therapy) as practiced in the 1970s was, contrary to previous beliefs, likely to be effective, the practice in high-income countries has been to use LHRH agonists to achieve the “same” outcomes—ovarian function suppression and chronic tumor growth factor reduction.[57] On the benefit side for LHRH treatment, reversibility is touted as important. This benefit is less certain when the question of optimal duration of therapy is considered. In prostate cancer, clinicians often continue LHRH therapy indefinitely. On the cost side for LHRH agonists, inconvenience and the need to assess for biologic effect are practical considerations, tied together with the major issue of economic cost. At $500 or more per month, a year of LHRH treatment is $6,000 in direct costs, leading to costs of $18,000 and $30,000 for 3 and 5 years of therapy, respectively.
The limited surgical oophorectomy data have allowed this LHRH approach to be promulgated as the standard of care worldwide, a standard that is not practical for the majority of women who need treatment. In the face of the available data, it is inappropriate and ethically untenable to continue this stance. Surgical oophorectomy should be the global standard of care for premenopausal women with hormone receptor–positive tumors.
Primary Tumor Removal and ‘Surgical Stress’ in Solid Tumor Management
For many years it has been known that removal of primary tumors is associated with facilitation of the growth of micrometastatic disease. Hrushesky and colleagues have highlighted the often observed increase and peak in hazard for the appearance of clinical metastatic disease in the immediate 2 to 3 years following removal of primary breast cancers. These investigators hypothesized that perioperative factors can be manipulated to decrease this hazard.[58] Despite confirming data in various studies that this hazard peak is not a statistical artifact and must be anchored by the event of primary tumor removal, primary breast surgery has continued to be seen as a technical intervention.
Reference GuideExploratory early and longer-term data have suggested that concurrent (same day) surgical oophorectomy and primary breast surgery is characterized by significant benefit from oophorectomies done in the luteal phase of the menstrual cycle.[59,60] We have offered a “progesterone trigger hypothesis” to explain this observation: Rapid decreases in progesterone blood levels in the luteal phase of the menstrual cycle with oophorectomy lead to “downstream” angiogenic protein changes that block micrometastatic growth.[61] A recent elegant laboratory research report has offered complementary evidence that perioperative, proangiogenic surgical stress–induced changes can be manipulated with reductions in tumor growth.[62] These observations all strongly suggest that greater attention to perioperative tumor biology growth models is warranted. We have two phase III proof-of -principle clinical trials in breast cancer testing our oophorectomy timing hypothesis.
Conclusions
The descriptive epidemiology of breast cancer—in terms of global case burdens, now predominantly an Asian and premenopausal disease—and the realization that the majority of the available biologic and treatment data come from high-income populations with northern European genetic backgrounds, should temper our discussions of breast cancer treatment. Tumor specimen selection and management before hormonal receptor testing are critical in influencing the likelihood of finding the presence of estrogen and progesterone receptor proteins. Both clinicians and patients should view hormone receptor–positive breast cancer as a commonly chronic disease.
In premenopausal women, combined hormonal therapy with ovarian ablation or suppression and tamoxifen therapy is the standard of care, and the ongoing SOFT and TEXT studies are very unlikely to provide support otherwise. The pharmacogenetic data with respect to tamoxifen are currently insufficient to dictate clinical practice. Specific prospective trials investigating the hypothesis that endoxifen concentrations in individual patients predict therapeutic efficacy are urgently needed. The high economic cost of LHRH treatment compared to that of surgical oophorectomy, given repeatedly demonstrated comparability of therapeutic effects, suggest that surgical treatment should be the standard of care. Finally, perioperative primary tumor biology warrants significantly more attention as we seek better approaches to breast cancer control that are practical and inexpensive, and produce limited side effects.
Add your own comment
Neil Friedman said:
There was a recent presentation, I believe from San Antonio, that most of the benefit for ovarian suppression in premenopausal women was in the younger patients, and that after age 35-40, it added little. I am confused. Neil S.Friedman MD Tel Hashomer Medical Center Israel
The Article Reviewed
Understanding the Issues
Aron Goldhirsch and Karen N. Price
Incorporating Clinical Experience
Saira Nasim and Kathleen I. Pritchard
http://www.cancernetwork.com/display/article/10...
p.s. I should mention that I did not read that medical journal article, nor the two articles that commented on the lead article (because my Mom is post-menopausal, and the article is regarding PRE-menopausal patients)… so I am not endorsing or recommending what it says (because I don't know what it says)… I just copied you in case you might be interested in seeing it, because the title sounded relevant to your case (“Seven Considerations for Adjuvant Hormonal Therapy in Premenopausal Women — Seven areas of provocative data that should inform approaches to adjuvant therapy”). Cheers!
I see that the links to the accompanying “review articles” (the responses/ commentaries from other doctors who in some part dispute/ disagree with that lead article from ONCOLOGY) did not transfer as links, so I will copy you on the text of each of those. Again, I have not read these (because my Mom is not PRE-menopausal), but if I already copied you on one side of the debate, then I guess I should also copy you on the (apparently) dissenting voices on the other side of the debate. Voila:
The Richard Love Article Reviewed
Understanding the Issues
By Aron Goldhirsch and Karen N. Price
ONCOLOGY. Vol. 24 No. 4
The Love Article Reviewed
Adjuvant Endocrine Therapy in Premenopausal Women With Operable Breast Cancer:
April 9, 2010
Aron Goldhirsch, MD
Director, Department of Medicine
European Institute of Oncology
Milan, Italy
Karen N. Price, BS
Director, Scientific Administration
IBCSG Statistical Center
Boston, Massachusetts
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Dr. Richard Love, in response to a recent review article, has prepared a commentary that implies that such reviews are often lacking in breadth because they only describe recent and current large clinical trials. It is understandable that a scholar like Dr. Love, who has made clinically relevant contributions in the treatment of younger women with breast cancer, focuses the attention of the reader on issues relating to therapies for this cohort. Dr. Love describes seven areas that are often not addressed in review articles, often criticizing clinical trial designs and their limited geographic populations along the way.
We agree that there is a body of “other provocative and emerging data” that may be relevant to clinical practice and should be discussed, but maintain that clinical trials provide the bulk of the evidence for treatment-based decision-making. We would in fact add to his list of issues relevant to the study of treatments for this disease.
Limited Research
Research and development of adjuvant therapies for premenopausal women with endocrine-responsive breast cancer is unfortunately lacking. Adjuvant endocrine therapy for premenopausal women with early breast cancer deserves the attention of the oncology community. Most of the progress for patients with endocrine-responsive disease that guides us today on type, sequence, combination, and duration of treatments has been made in the postmenopausal setting. Very few studies have been designed and activated for this population of premenopausal patients.
Besides investigations like the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen/Exemestane Trial (TEXT), mentioned by Dr. Love, very little has been done to better investigate potential endocrine treatment approaches. The majority of phase I and II trials on new compounds (together with endocrine therapies) exclude premenopausal women. Endocrine agents like gonadotropin-releasing hormone (GnRH) antagonists, fulvestrant (Faslodex), other selective estrogen receptor modulators (SERMs), and progestins were never systematically investigated in premenopausal women, and their use in the adjuvant setting was therefore not taken into consideration.
Study Distinctions
Adjuvant effects of combined tamoxifen and amenorrhea (through ovarian suppression) still amount to an open question for many. The prospectively designed SOFT trial should provide an answer to the question of whether the combined use of ovarian suppression plus tamoxifen (or exemestane [Aromasin]) is better than tamoxifen alone. But there is evidence from a retrospective analysis of International Breast Cancer Study Group (IBCSG) trial 13-93 that combined tamoxifen and amenorrhea is better than tamoxifen alone.[1] Specifically, the treatment outcomes of 332 patients who received tamoxifen were analyzed for chemotherapy-induced amenorrhea (n = 286) or no amenorrhea (n = 46). The 5-year disease-free survival was 80% for the combined-treatment group and 65% for the tamoxifen-without-amenorrhea group (P = .05).
For those who considered the SOFT question already answered by such retrospective studies, the TEXT trial may be of greater interest for the premenopausal population with endocrine-responsive disease. In this trial, all patients undergo ovarian function suppression and the trial question relates to the efficacy of tamoxifen vs exemestane. Dr. Love, in lumping SOFT and TEXT together, misses this difference between the two trials.
False-Negative vs False-Positive ER Findings
Steroid hormone receptor determination by immune-histochemistry is required to properly identify patients who will benefit from endocrine therapy. Dr. Love recognizes the importance of false-negative estrogen receptor (ER) determination. Underestimated ERs in the tumor might lead to the denial of proper endocrine therapy for some patients.[2] What Dr. Love does not mention is the fact that there is a small but significant proportion of false-positive ER determinations, estimated to be around 2.6% (Viale G, BIG 1-98 trial, personal communication). An ER-positive report on a tumor that is actually ER-negative may lead to the patient receiving an ineffective (and possibly deleterious) endocrine therapy.
Treatment Duration
Lastly, we would comment on the suggestion that endocrine-responsive breast cancer be considered a chronic disease, with the implication that treatments should continue long term. Evidence to guide decisions about treatment duration is lacking, and again mostly derived from trials in postmenopausal women. In premenopausal women, research studying possible pregnancy after a period of adjuvant endocrine therapy has been neglected. The opportunity to continue with a normal life while reducing most of the risk of relapse should be the goal of investigations in this cohort in the future.
—Aron Goldhirsch, MD
—Karen N. Price, BS
This commentary refers to the following article from ONCOLOGY:
Adjuvant Hormonal Therapy in Premenopausal Women With Operable Breast Cancer: Not-So-Peripheral Perspectives
And here is the text from the second “review” article that was published below the lead article — another commentary that in some way disputes/ disagrees with the lead article. (I will also include a link at the end:)
ONCOLOGY. Vol. 24 No. 4
Focus on Breast Cancer
The Richard Love Article Reviewed
Adjuvant Hormonal Therapy for Premenopausal Breast Cancer:
Incorporating Clinical Experience
By Saira Nasim, MBBS, MRCPI
Clinical Research Fellow
Sunnybrook Odette Cancer Centre
Kathleen I. Pritchard, MD, FRCPC
Senior Scientist, Sunnybrook Odette Cancer Centre
Professor, Departments of Medicine, Health Policy
Measurement and Evaluation (HPME), and Public Health Sciences
University of Toronto
Toronto, Canada
| April 9, 2010
The article “Adjuvant Hormonal Therapy in Premenopausal Women With Operable Breast Cancer: Not-So-Peripheral Perspectives” by Richard Love, published in this issue of ONCOLOGY, raises a number of important practice issues in the setting of adjuvant hormonal therapy for premenopausal women. This paper was written partially in response to Dr. Pritchard’s publication, “Ovarian Suppression/Ablation in Premenopausal ER-Positive Breast Cancer Patients,” which appeared in the January 2009 issue of this journal.[1] We would like first to comment on the general differences between that article and Dr. Love’s current paper.
The January 2009 paper was designed as an evidence-based review of the literature. In practice, however, we all must make decisions based on less robust data or in the absence of data. Furthermore, many of the issues raised by Dr. Love involve considerable, if not level 1, clinical and scientific evidence. In the current Program in Evidence-Based Care (PEBC) of Cancer Care Ontario (CCO), an explicit section is devoted to conclusions that extrapolate from evidence-based data to incorporate clinician concerns or experience from clinical practice.[2] Much of the information highlighted by Dr. Love fits into this category. These sections have been added to the CCO PEBC Guidelines because it is believed that there are often important approaches that may come only from the consensus of experts or from practical clinical experience. Several of the points Dr. Love raises belong in this category. In the following commentary, we respond to his seven issues.
Descriptive Epidemiologic Data of Breast Cancer Globally
We agree with Dr Love’s observation on changing global patterns in the incidence of breast cancer. It is no longer a disease confined to the Western world. Over a million new cases of breast cancer will be diagnosed worldwide each year. Low- and middle-income countries will be burdened by nearly half of these new breast cancer cases, which occur predominantly in premenopausal women, in contrast to the predominance of postmenopausal cases in affluent countries. Lack of data on reproductive risk factors, genetics, and metabolic profile in the majority of these women adds to the complexity of the global breast cancer burden worldwide. Screening and treatment approaches may also be quite different from those for Caucasian women living in Western countries. Treatment modalities such as tamoxifen or surgical oophorectomy, which are both efficacious and cost-effective, are important and acceptable therapeutic options for women in the low- and middle-income countries.
Tumor Hormonal Receptor Testing
Issues around quality control in this area have recently been widely publicized.[3,4] The upcoming American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) estrogen receptor (ER)/progesterone receptor (PR) guideline addresses many of these issues, including tissue fixation, choice of antibody, method for interpretation of immunostaining, and other issues to ensure validation and standardization for ER testing.[5] Love’s discussion of the fact that 10% more tumors are found to be hormone receptor–positive in core biopsies than in lumpectomy and mastectomy specimens, is probably an illustration of the time to penetration and fixation of tumor tissues, which, as he describes, is probably longer in larger specimens. Clearly, if receptor analysis were done on cores only or on cores and lumpectomy/mastectomy specimens, more information could be obtained. This suggestion should indeed be further considered, and additional data regarding this matter would be useful.
Hormone Receptor–Positive Breast Cancer Is a Chronic Disease
As we have collected and considered additional data concerning interim follow-up and treatment of hormone-positive breast cancer patients over the past 5 to 15 years, a paradigm shift has occurred. As Love points out, data such as those from the Early Breast Cancer Trialists’ Collaborative Group[6] and Saphner et al[7] clearly support this view. Unfortunately, lack of funding for long-term follow-up in many clinical cooperative groups has resulted in the discontinuation of follow-up after 10 years in many adjuvant trials. This is unfortunate in what is clearly a chronic disease for which long-term follow-up is becoming more, not less, important. Funding for long-term classic trial follow-up or new and cheaper approaches to long-term follow-up should clearly be explored. Excellent work in this regard has been done in some of the Scandinavian countries, where data from large randomized trials were matched with registry data to produce interesting outcome and toxicity results.[8]
Combined Ovarian Suppression or Ablation and Tamoxifen Therapy Is Standard of Care
Here we must take exception with Dr. Love. We agree that Dr. Gnant’s Austrian Breast Cancer Study Group (ABCSG) trial,[9] at least suggests that there is no benefit to the use of an aromatase inhibitor (AI) plus ovarian suppression in comparison to tamoxifen plus ovarian suppression. However, we think these are insufficient data to establish equivalence and that further follow-up of this study and/or additional data would be helpful.
Many have hypothesized that a luteinizing hormone-releasing hormone (LHRH) agonist plus an AI would be superior, assuming that ovarian suppression with an LHRH analog is always complete. This is clearly not so.[10,11] It is well known that 5% to 10% of normal premenopausal women receiving an LHRH agonist may override the agonist, particularly when 3-monthly LHRH analogs are given.[12] AIs, by lowering peripheral estrogen provide negative feedback to the pituitary, and in the premenopausal setting this feedback loop may result in overproduction of estrogen by the intact ovaries. Thus, an LHRH agonist plus an AI is, theoretically at least, unsafe, and in any case has not been adequately shown to be equivalent to tamoxifen plus an LHRH agonist. It is important to recognize, therefore, that clinicians should not use an LHRH agonist plus an AI in premenopausal women outside of clinical trials.
We also somewhat disagree with Love’s interpretation of the mini–meta-analysis[13] of the combination of LHRH plus tamoxifen compared to an LHRH agonist alone. This is a small meta-analysis driven almost completely by one study.[14] While it appears to suggest that an LHRH agonist plus tamoxifen is better in the metastatic setting than an LHRH agonist alone, the comparison to an LHRH agonist followed by tamoxifen vs the two used concurrently has not been well made. As a result, few clinicians have incorporated this concurrent combination into the metastatic setting. We believe that posing this question in the adjuvant setting will make both efficacy and toxicity much more clear. The Suppression of Ovarian Function Trial (SOFT) data will add to the evidence available regarding this question, but even SOFT may be somewhat underpowered. Since SOFT has now completed accrual, one can—and we certainly do—discuss the use of tamoxifen alone, ovarian suppression or ablation alone, or the combination as therapeutic options in all premenopausal women with hormonally responsive breast cancer in the adjuvant setting.
Pharmacogenetic Hypotheses With Tamoxifen
Dr. Love has succinctly summarized the issues of tamoxifen pharmacogenomics. Side effects associated with tamoxifen and variation in response have been identified since initial drug development. The clinical relevance of CYP2D6 genotyping remains uncertain, as currently available evidence is contradictory. None of the published studies have assessed the association of endoxifen, the most important tamoxifen metabolite, with clinical outcomes in breast cancer patients. We agree that this remains a matter for further study and requires evaluation in terms of the clinical utility of monitoring endoxifen levels when steady-state metabolite concentrations are reached after 4 weeks of continuous tamoxifen therapy.[15] It may be more useful to determine CYP2D6 genotype prior to commencing tamoxifen rather than to attempt therapeutic drug monitoring. Additional data from well designed clinical trials will clearly be useful in this setting before a change in practice is advocated.
Ethical Issues in Ovarian Suppression vs Ablative Treatment
In a single payer and perhaps more fiscally accountable system such as the Canadian or Ontario Health Care System, preference toward surgical oophorectomy, rather than ongoing LHRH agonists, is clear. However, it is our practice that LHRH agonists may be used to test a patient’s tolerance to ovarian ablation before performing surgery and/or in settings in which preservation of subsequent ovarian function is desired in order to facilitate pregnancy or for other reasons. Nonetheless, surgical oophorectomy is definitely preferable—both clinically and financially—once permanent oophorectomy is decided on between patient and physician. In many patients who are over 40 or 45 years old and/or who do not desire future pregancies, this is an easy decision. We do believe however, that the use of LHRH agonists should remain an option for women who desire only temporary ablation for a variety of personal reasons. Nonetheless, as Dr. Love points out, this approach raises the issue of length of administration of LHRH agonists, which has not been well studied.
Importance of Primary Tumor Removal and Surgical Stress in Solid Tumor Management
The impact of the timing of breast surgery according to the phase of menstrual cycle has been a controversial issue, and current available evidence is contradictory.[16-19] Problems in evaluating this hypothesis are exacerbated by the difficulty of accurate assessment of the hormonal status of the patient as well as the challenge of scheduling a patient’s surgery to fit with her hormonal cycle, particularly with tight operating schedules, and the frequent disruption of hormonal cycling after breast cancer diagnosis. While this hypothesis has strong preclinical support and may be correct, we suspect it will remain poorly tested and not practical for regular usage.
Conclusion
Dr. Love raises a number of important issues. These include viewing breast cancer as a worldwide, rather than a Western disease, as well as the role of clinician consensus and experience in informing physical practice. Clearly, further investigation of concurrent combination vs sequential hormonal approaches in adjuvant therapy and of the pharmacogenetics of tamoxifen will provide additional evidence in these important areas.
—Saira Nasim, MBBS, MRCPI
—Kathleen I. Pritchard, MD, FRCPC
http://www.cancernetwork.com/display/article/10...