Current Controversial Concerns
Guideline Calls Routine Pelvic Exams Unnecessary
By Roni Caryn Rabin : NY Times : June 30, 2014
Doctors should stop performing routine pelvic exams, a key component of regular physicals for women, an influential medical group said Monday.
There is no evidence that such pelvic exams are useful and plenty to suggest that the procedure provokes fear, anxiety and pain in many women, the American College of Physicians said in a new practice guideline for doctors.
The college’s guideline was published in the Annals of Internal Medicine and was accompanied by an article reviewing the scientific evidence. The recommendation applies only to routine checkups for healthy women, not to women who visit the doctor’s office with medical complaints or who are pregnant.
“The pelvic exam has become a yearly ritual, but I think it’s something women don’t necessarily look forward to,” said Dr. Sandra Adamson Fryhofer, an internist in Atlanta who is a former president of the college. “A lot of women dread it.”
The new recommendation contradicts guidelines from the American College of Obstetricians and Gynecologists, which immediately reiterated its support for yearly pelvic exams.
A pelvic exam consists of three elements: inspection of the external genitalia, examination of the vagina and cervix, and the bimanual examination, in which the physician inserts two gloved fingers into a woman’s vagina and, with the other hand, presses down on her abdomen to check the shape and size of her uterus, ovaries and fallopian tubes.
The exam takes up time during an annual physical and often requires the presence of a chaperone in the room, which raises costs.
The American College of Physicians reviewed studies of the procedure and concluded that pelvic exams were not accurate diagnostic screening tests for ovarian cancer. A dozen studies have suggested that many women experience pain or discomfort during the exams, and that they may be particularly traumatic for women who have been sexually assaulted.
The reviewers said that they could not even locate studies that had assessed whether routine pelvic exams of asymptomatic women could reduce death or disease from ovarian and other cancers, or benefit women with common benign conditions such as pelvic inflammatory disease, fibroids or warts.
Until about a decade ago, physicians routinely performed pelvic exams before prescribing oral contraceptives, and they used the exams to screen women for sexually transmitted infections and obtain cultures for testing. Those practices have largely been abandoned, and urine samples are now used to test for sexually transmitted infections.
In recent years some experts have suggested that pelvic exams are so discomforting that they may deter women from going to the doctor altogether.
Gynecologists agree that pelvic exams are not good tools for screening for ovarian cancer, which is notoriously difficult to diagnose. But, they say, experienced physicians can use pelvic exams to find other problems, such as noncancerous fibroids, and to identify changes linked to urinary incontinence and sexual dysfunction.
“Not everything we do in life can be studied in a randomized trial powered to find a scientifically valid answer one way or another,” said Dr. Barbara S. Levy, vice president for health policy at the obstetricians and gynecologists’ group.
“I’m not sure there’s evidence to support most of what we do on physical exams,” Dr. Levy added. “Lack of evidence does not mean lack of value.”
The new guideline comes as more routine procedures are critically evaluated in light of scientific studies, part of a move toward evidence-based medicine. Over the past few years, several new sets of guidelines have urged scaling back screening procedures for women in particular.
In 2009, the United States Preventive Services Task Force recommended postponing routine mammograms to detect breast cancer until age 50, provoking wide controversy. Many women have ignored the advice.
More recently, the task force, the American Cancer Society and the obstetricians and gynecologists’ group have recommended that, with some exceptions, women ages 21 to 65 should receive Pap smears every three years instead of annually.
By Roni Caryn Rabin : NY Times : June 30, 2014
Doctors should stop performing routine pelvic exams, a key component of regular physicals for women, an influential medical group said Monday.
There is no evidence that such pelvic exams are useful and plenty to suggest that the procedure provokes fear, anxiety and pain in many women, the American College of Physicians said in a new practice guideline for doctors.
The college’s guideline was published in the Annals of Internal Medicine and was accompanied by an article reviewing the scientific evidence. The recommendation applies only to routine checkups for healthy women, not to women who visit the doctor’s office with medical complaints or who are pregnant.
“The pelvic exam has become a yearly ritual, but I think it’s something women don’t necessarily look forward to,” said Dr. Sandra Adamson Fryhofer, an internist in Atlanta who is a former president of the college. “A lot of women dread it.”
The new recommendation contradicts guidelines from the American College of Obstetricians and Gynecologists, which immediately reiterated its support for yearly pelvic exams.
A pelvic exam consists of three elements: inspection of the external genitalia, examination of the vagina and cervix, and the bimanual examination, in which the physician inserts two gloved fingers into a woman’s vagina and, with the other hand, presses down on her abdomen to check the shape and size of her uterus, ovaries and fallopian tubes.
The exam takes up time during an annual physical and often requires the presence of a chaperone in the room, which raises costs.
The American College of Physicians reviewed studies of the procedure and concluded that pelvic exams were not accurate diagnostic screening tests for ovarian cancer. A dozen studies have suggested that many women experience pain or discomfort during the exams, and that they may be particularly traumatic for women who have been sexually assaulted.
The reviewers said that they could not even locate studies that had assessed whether routine pelvic exams of asymptomatic women could reduce death or disease from ovarian and other cancers, or benefit women with common benign conditions such as pelvic inflammatory disease, fibroids or warts.
Until about a decade ago, physicians routinely performed pelvic exams before prescribing oral contraceptives, and they used the exams to screen women for sexually transmitted infections and obtain cultures for testing. Those practices have largely been abandoned, and urine samples are now used to test for sexually transmitted infections.
In recent years some experts have suggested that pelvic exams are so discomforting that they may deter women from going to the doctor altogether.
Gynecologists agree that pelvic exams are not good tools for screening for ovarian cancer, which is notoriously difficult to diagnose. But, they say, experienced physicians can use pelvic exams to find other problems, such as noncancerous fibroids, and to identify changes linked to urinary incontinence and sexual dysfunction.
“Not everything we do in life can be studied in a randomized trial powered to find a scientifically valid answer one way or another,” said Dr. Barbara S. Levy, vice president for health policy at the obstetricians and gynecologists’ group.
“I’m not sure there’s evidence to support most of what we do on physical exams,” Dr. Levy added. “Lack of evidence does not mean lack of value.”
The new guideline comes as more routine procedures are critically evaluated in light of scientific studies, part of a move toward evidence-based medicine. Over the past few years, several new sets of guidelines have urged scaling back screening procedures for women in particular.
In 2009, the United States Preventive Services Task Force recommended postponing routine mammograms to detect breast cancer until age 50, provoking wide controversy. Many women have ignored the advice.
More recently, the task force, the American Cancer Society and the obstetricians and gynecologists’ group have recommended that, with some exceptions, women ages 21 to 65 should receive Pap smears every three years instead of annually.
Medical Procedures May Be Useless, or Worse
By Nicholas Bakalar : NY Times : July 26, 2013
We usually assume that new medical procedures and drugs are adopted because they are better. But a new analysis has found that many new techniques and medicines are either no more effective than the old ones, or worse. Moreover, many doctors persist in using practices that have been shown to be useless or harmful.
Scientists reviewed each issue of The New England Journal of Medicine from 2001 through 2010 and found 363 studies examining an established clinical practice. In 146 of them, the currently used drug or procedure was found to be either no better, or even worse, than the one previously used. The report appears in the August issue of Mayo Clinic Proceedings.
More than 40 percent of established practices studied were found to be ineffective or harmful, 38 percent beneficial, and the remaining 22 percent unknown. Among the practices found to be ineffective or harmful were the routine use of hormone therapy in postmenopausal women; high-dose chemotherapy and stem cell transplant, a complex and expensive treatment for breast cancer that was found to be no better than conventional chemotherapy; and intensive glucose lowering in Type 2 diabetes patients in intensive care, which not only failed to reduce cardiovascular events but actually increased mortality.
In some instances, doctors routinely refused to give beneficial therapies despite a lack of evidence that they were harmful. Vaccines were unnecessarily withheld from multiple sclerosis patients in the belief that they increased flare-ups; women with lupus were denied oral contraceptives for fear they increased the severity of the disease; and epidural anesthesia was delayed during childbirth on the theory it increased the rate of Caesarean sections. Yet good studies showed that none of these fears was justified..
“Contradicted practices don’t disappear immediately,” said the lead author, Dr. Vinay Prasad. “There’s an inertia, a 10-year period of time when the contradicted procedure continues to be practiced.”
Dr. William E. Boden, chief of medicine at the Stratton VA Medical Center in Albany, who was not involved in the work, found the study useful and provocative. “It’s challenging us to look at things we’ve done and attempt to find whether there’s evidence to support their use,” he said. “There’s going to be increasing pressure to come forward with making sure that the health care dollars we’re allocating are being well utilized.”
Dr. Prasad, chief fellow in medical oncology at the National Cancer Institute, said that new medical appliances present a special problem. “Devices are particularly bad because they can be approved if they’re similar to ones already on the market,” he said. He cited as an example the Swan-Ganz catheter, a device threaded into the heart to monitor heart function and blood flow. It gives accurate information, Dr. Prasad said, “but that information doesn’t help. We continue to introduce new catheters all the time, lacking good evidence that they work. This is a tremendous waste of resources.”
Often doctors persist with procedures that lack evidence because they seem to make sense, Dr. Prasad said. “They all sound good if you talk about the mechanisms,” he said. “You have cholesterol-clogged arteries, it makes sense that if you open them up it will help. But when that was studied, it didn’t improve survival.”
Patients, too, like to talk about mechanisms, Dr. Prasad added. “They tend to gravitate toward the nuts and bolts — what does it do, how does it work?” he said. “But the real question is: Does it work? What evidence is there that it does what you say it does? What trials show that it actually works? You shouldn’t ask how does it work, but whether it works at all.”
By Nicholas Bakalar : NY Times : July 26, 2013
We usually assume that new medical procedures and drugs are adopted because they are better. But a new analysis has found that many new techniques and medicines are either no more effective than the old ones, or worse. Moreover, many doctors persist in using practices that have been shown to be useless or harmful.
Scientists reviewed each issue of The New England Journal of Medicine from 2001 through 2010 and found 363 studies examining an established clinical practice. In 146 of them, the currently used drug or procedure was found to be either no better, or even worse, than the one previously used. The report appears in the August issue of Mayo Clinic Proceedings.
More than 40 percent of established practices studied were found to be ineffective or harmful, 38 percent beneficial, and the remaining 22 percent unknown. Among the practices found to be ineffective or harmful were the routine use of hormone therapy in postmenopausal women; high-dose chemotherapy and stem cell transplant, a complex and expensive treatment for breast cancer that was found to be no better than conventional chemotherapy; and intensive glucose lowering in Type 2 diabetes patients in intensive care, which not only failed to reduce cardiovascular events but actually increased mortality.
In some instances, doctors routinely refused to give beneficial therapies despite a lack of evidence that they were harmful. Vaccines were unnecessarily withheld from multiple sclerosis patients in the belief that they increased flare-ups; women with lupus were denied oral contraceptives for fear they increased the severity of the disease; and epidural anesthesia was delayed during childbirth on the theory it increased the rate of Caesarean sections. Yet good studies showed that none of these fears was justified..
“Contradicted practices don’t disappear immediately,” said the lead author, Dr. Vinay Prasad. “There’s an inertia, a 10-year period of time when the contradicted procedure continues to be practiced.”
Dr. William E. Boden, chief of medicine at the Stratton VA Medical Center in Albany, who was not involved in the work, found the study useful and provocative. “It’s challenging us to look at things we’ve done and attempt to find whether there’s evidence to support their use,” he said. “There’s going to be increasing pressure to come forward with making sure that the health care dollars we’re allocating are being well utilized.”
Dr. Prasad, chief fellow in medical oncology at the National Cancer Institute, said that new medical appliances present a special problem. “Devices are particularly bad because they can be approved if they’re similar to ones already on the market,” he said. He cited as an example the Swan-Ganz catheter, a device threaded into the heart to monitor heart function and blood flow. It gives accurate information, Dr. Prasad said, “but that information doesn’t help. We continue to introduce new catheters all the time, lacking good evidence that they work. This is a tremendous waste of resources.”
Often doctors persist with procedures that lack evidence because they seem to make sense, Dr. Prasad said. “They all sound good if you talk about the mechanisms,” he said. “You have cholesterol-clogged arteries, it makes sense that if you open them up it will help. But when that was studied, it didn’t improve survival.”
Patients, too, like to talk about mechanisms, Dr. Prasad added. “They tend to gravitate toward the nuts and bolts — what does it do, how does it work?” he said. “But the real question is: Does it work? What evidence is there that it does what you say it does? What trials show that it actually works? You shouldn’t ask how does it work, but whether it works at all.”
When Lyme Disease Lasts and Lasts
By Jane E. Brody : NY Times : July 8, 2013
Chronic Lyme disease is a highly controversial catch-all term for a host of long-lasting symptoms that may or may not stem from prior infection with the bacterium that causes acute Lyme disease. Often misdiagnosed and mistreated, chronic Lyme disease leaves thousands of people physically and mentally debilitated and without a medically established recourse.
Mary Rasenberger, 51, a New York lawyer, experienced “a series of ailments going back 10 years.” She was finally given a diagnosis of chronic Lyme disease last summer after having been told that she had multiple sclerosis.
Her long-term symptoms were “aching joints, headaches and indescribable fatigue” that made her miserable and unable to exercise. In the last few years, two additional symptoms developed: neuropathy in her limbs and face, and vision problems. In an interview, she said she “woke up every day feeling sick”; if she became overheated, she felt as if she had the flu.
Yet a test for Lyme disease came back negative. Desperate, she finally consulted a Lyme “specialist,” one of a number of doctors who treat patients with symptoms like Ms. Rasenberger’s with long-term antibiotics, despite the fact that such a regimen has shown no significant or lasting benefit in controlled clinical trials. These trials involved randomly assigning patients to the antibiotic Rocephin (often administered intravenously) or a placebo, with neither patients nor those evaluating their symptoms aware of who got what.
Still, after several months on antibiotics Ms. Rasenberger, like many similar patients, said she felt “completely healthy for the first time in years.” Each time she tries to stop the medication, her debilitating symptoms return.
Reports like Ms. Rasenberger’s are hardly unusual, and experts now realize that some people who get Lyme disease go on to develop a chronic illness even if their initial infection was promptly diagnosed and correctly treated. Approximately 10 percent to 15 percent of people who are treated for medically documented Lyme disease develop persistent or recurrent symptoms of fatigue, musculoskeletal pain and cognitive complaints.
The condition is known as post-treatment Lyme disease syndrome, or PTLDS. “It is a real disorder, although nobody really knows what’s happening,” Dr. John N. Aucott, an infectious disease specialist in Lutherville, Md., said in an interview.
“A lot of patients have been told they’re not really sick, just tired or depressed,” he added. “But this is not normal fatigue, and it’s not caused by depression” — although depression certainly can result from the patient’s seriously diminished quality of life.
Antibiotic therapy for PTLDS is based on disputed reports that these patients may harbor hidden reservoirs of the spirochete causing Lyme disease, Borrelia burgdorferi, long after their initial treatment. But researchers who have studied the therapy have found it of little or no benefit, and many say the regimen is fraught with hazards that could be even worse than the illness.
Risks include the development of an antibiotic-resistant infection, intractable diarrhea, kidney or liver damage and, as happened to a 30-year-old woman treated with an antibiotic through a catheter, death from a systemic infection called sepsis.
People with PTLDS are not hypochondriacs seeking attention or sluggards wanting to avoid work or chores, Dr. Aucott said, though they may benefit from psychotherapy that helps them cope better with their symptoms.
“These are high-functioning people — couch potatoes don’t get Lyme disease,” he said. “They are not crazy, and the doctors who treat them are not evil. These are desperate people trying to get better, and well-intentioned doctors who are trying to help them.”
But until the causes of PTLDS are discerned, it will be difficult for researchers to find effective therapies. Among the possible causes of the syndrome are prolonged post-infection fatigue and an autoimmune reaction to the infecting organism, according to a recent book by Dr. Adriana Marques of the National Institute of Allergy and Infectious Diseases.
As for why some people with PTLDS seem to benefit from intensive antibiotic therapy, at least temporarily, Dr. Aucott suggested a few theories. The antibiotics may have an anti-inflammatory effect that relieves pain and swelling. Alternatively, patients may have a low-level, persistent infection that is temporarily suppressed by antibiotics — but not killed by them. Or it may be that some PTLDS patients experience a placebo effect, improving because they believe the treatment will help and because someone is finally taking their symptoms seriously.
Complicating the picture is the fact that some people with PTLDS symptoms apparently never had Lyme disease in the first place, Dr. Marques said in an interview. There are other infectious organisms — Epstein-Barr virus, for example — that can produce similar symptoms and may be the real culprits.
But experts cannot rule out Lyme spirochete as a cause, either. Many, if not most, people who are infected with it never know they have been bitten by the tiny deer tick that spreads the bacterium from animals to people. They may never develop or notice the red rash that can result. Even when a rash occurs, only one in five is the characteristic bull’s-eye associated with Lyme disease. Most are solid red and round or oval.
Such people may never receive treatment for the infection in its early stages and end up weeks, months, even years later with the kinds of symptoms that have plagued Ms. Rasenberger. Symptoms may develop gradually, as they did in my dog, which had minimal effects from a Lyme-carrying tick until nine months later, when he collapsed, unable to eat or drink on his own.
Both Dr. Aucott and Dr. Marques said more research is desperately needed if people are to get the help they need. “This is a huge disease that’s only going to get bigger, yet it receives only a tiny fraction of the N.I.H. budget,” Dr. Aucott said, referring to the National Institutes of Health.
Given the uncertainties about chronic Lyme disease, prevention is more important than ever. Avoid walking through brush and high grass. When hiking in the woods, camping, gardening or mowing the lawn, wear long, light-colored clothing and tuck pant legs into tightfitting socks. Spray exposed skin with a 20-percent DEET insecticide and clothing with permethrin. Remove clothes before coming back indoors, and wash and dry them separately.
Shower as soon as possible after being outdoors, using a washcloth or loofah, and check your body carefully, especially in skin folds, for attached ticks. They should be carefully removed with a tweezer without crushing them by pulling gently and steadily near the mouth. Then apply an antiseptic to the site.
Bigger Role Seen for Breast Cancer Drug
By Andrew Pollack : NY Times : December 5, 2012
The widely prescribed drug tamoxifen already plays a major role in reducing the risk of death from breast cancer. But a new study suggests that women should be taking the drug for twice as long as is now customary, a finding that could upend the standard that has been in place for about 15 years.
In the study, patients who continued taking tamoxifen for 10 years were less likely to have the cancer come back or to die from the disease than women who took the drug for only five years, the current standard of care.
“Certainly, the advice to stop in five years should not stand,” said Prof. Richard Peto, a medical statistician at Oxford University and senior author of the study, which was published in The Lancet on Wednesday and presented at the San Antonio Breast Cancer Symposium.
Breast cancer specialists not involved in the study said the results could have the biggest impact on premenopausal women, who account for a fifth to a quarter of new breast cancer cases. Postmenopausal women tend to take different drugs, but some experts said the results suggest that those drugs might be taken for a longer duration as well.
“We’ve been waiting for this result,” said Dr. Robert W. Carlson, a professor of medicine at Stanford University. “I think it is especially practice-changing in premenopausal women because the results do favor a 10-year regimen.”
Dr. Eric P. Winer, chief of women’s cancers at the Dana-Farber Cancer Institute in Boston, said that even women who completed their five years of tamoxifen months or years ago might consider starting on the drug again.
Tamoxifen blocks the effect of the hormone estrogen, which fuels tumor growth in estrogen receptor-positive cancers that account for about 65 percent of cases in premenopausal women. Some small studies in the 1990s suggested that there was no benefit to using tamoxifen longer than five years, so that has been the standard.
About 227,000 cases of breast cancer are diagnosed each year in the United States, and an estimated 30,000 of them are in premenopausal women with estrogen receptor-positive cancer and prime candidates for tamoxifen. But postmenopausal women also take tamoxifen if they cannot tolerate the alternative drugs, known as aromatase inhibitors.
The new study, known as Atlas, included nearly 7,000 women with ER-positive disease who had completed five years of tamoxifen. They came from about three dozen countries. Half were chosen at random to take the drug another five years, while the others were told to stop.
In the group assigned to take tamoxifen for 10 years, 21.4 percent had a recurrence of breast cancer in the ensuing 10 years, meaning the period 5 to 14 years after their diagnoses. The recurrence rate for those who took only five years of tamoxifen was 25.1 percent.
About 12.2 percent of those in the 10-year treatment group died from breast cancer, compared with 15 percent for those in the control group.
There was virtually no difference in death and recurrence between the two groups during the five years of extra tamoxifen. The difference came in later years, suggesting that tamoxifen has a carry-over effect that lasts long after women stop taking it.
Whether these differences are big enough to cause women to take the drug for twice as long remains to be seen.
“The treatment effect is real, but it’s modest,” said Dr. Paul E. Goss, director of breast cancer research at the Massachusetts General Hospital.
Tamoxifen has side effects, including endometrial cancer, blood clots and hot flashes, which cause many women to stop taking the drug. In the Atlas trial, it appears that roughly 40 percent of the patients assigned to take tamoxifen for the additional five years stopped prematurely.
Some 3.1 percent of those taking the extra five years of tamoxifen got endometrial cancer versus 1.6 percent in the control group. However, only 0.6 percent of those in the longer treatment group died from endometrial cancer or pulmonary blood clots, compared with 0.4 percent in the control group.
“Over all, the benefits of extended tamoxifen seemed to outweigh the risks substantially,” Trevor J. Powles of the Cancer Center London, said in a commentary published by The Lancet.
Dr. Judy E. Garber, director of the Center for Cancer Genetics and Prevention at Dana-Farber, said many women have a love-hate relationship with hormone therapies.
“They don’t feel well on them, but it’s their safety net,” said Dr. Garber, who added that the news would be welcomed by many patients who would like to stay on the drug. “I have patients who agonize about this, people who are coming to the end of their tamoxifen.”
Emily Behrend, who is a few months from finishing her five years on tamoxifen, said she would definitely consider another five years. “If it can keep the cancer away, I’m all for it,” said Ms. Behrend, 39, a single mother in Tomball, Tex. She is taking the antidepressant Effexor to help control the night sweats and hot flashes caused by tamoxifen.
Cost is not considered a huge barrier to taking tamoxifen longer because the drug can be obtained for less than $200 a year.
The results, while answering one question, raise many new ones, including whether even more than 10 years of treatment would be better still.
Perhaps the most important question is what the results mean for postmenopausal women. Even many women who are premenopausal at the time of diagnosis will pass through menopause by the time they finish their first five years of tamoxifen, or will have been pushed into menopause by chemotherapy.
Postmenopausal patients tend to take aromatase inhibitors like anastrozole or letrozole, which are more effective than tamoxifen at preventing breast cancer recurrence, though they do not work for premenopausal women.
Mr. Peto said he thought the results of the Atlas study would “apply to endocrine therapy in general,” meaning that 10 years of an aromatase inhibitor would be better than five years. Other doctors were not so sure.
The Atlas study was paid for by various organizations including the United States Army, the British government and AstraZeneca, which makes the brand-name version of tamoxifen.
U.S. Panel Advises Against Routine Use of Prostate Test
By Gardiner Harris : NY Times October 6, 2011
Healthy men should no longer receive a P.S.A. blood test to screen for prostate cancer because the test does not save lives over all and often leads to more tests and treatments that needlessly cause pain, impotence and incontinence in many, a key government health panel has decided.
The draft recommendation, by the United States Preventive Services Task Force and due for official release next week, is based on the results of five well-controlled clinical trials and could substantially change the care given to men 50 and older. There are 44 million such men in the United States, and 33 million of them have already had a P.S.A. test — sometimes without their knowledge — during routine physicals.
The task force’s recommendations are followed by most medical groups. Two years ago the task force recommended that women in their 40s should no longer get routine mammograms, setting off a firestorm of controversy. The recommendation to avoid the P.S.A. test is even more forceful and applies to healthy men of all ages.
“Unfortunately, the evidence now shows that this test does not save men’s lives,” said Dr. Virginia Moyer, a professor of pediatrics at Baylor College of Medicine and chairwoman of the task force. “This test cannot tell the difference between cancers that will and will not affect a man during his natural lifetime. We need to find one that does.”
But advocates for those with prostate cancer promised to fight the recommendation. Baseball’s Joe Torre, the financier Michael Milken and Rudolph W. Giuliani, the former New York City mayor, are among tens of thousands of men who believe a P.S.A. test saved their lives.
The task force can also expect resistance from some drug makers and doctors. Treating men with high P.S.A. levels has become a lucrative business. Some in Congress have criticized previous decisions by the task force as akin to rationing, although the task force does not consider cost in its recommendations.
“We’re disappointed,” said Thomas Kirk, of Us TOO, the nation’s largest advocacy group for prostate cancer survivors. “The bottom line is that this is the best test we have, and the answer can’t be, ‘Don’t get tested.’ ”
But that is exactly what the task force is recommending. There is no evidence that a digital rectal exam or ultrasound are effective, either. “There are no reliable signs or symptoms of prostate cancer,” said Dr. Timothy J. Wilt, a member of the task force and a professor of medicine at the University of Minnesota. Frequency and urgency of urinating are poor indicators of disease, since the cause is often benign.
The P.S.A. test, routinely given to men 50 and older, measures a protein — prostate-specific antigen — that is released by prostate cells, and there is little doubt that it helps identify the presence of cancerous cells in the prostate. But a vast majority of men with such cells never suffer ill effects because theircancer is usually slow-growing. Even for men who do have fast-growing cancer, the P.S.A. test may not save them since there is no proven benefit to earlier treatment of such invasive disease.
As the P.S.A. test has grown in popularity, the devastating consequences of the biopsies and treatments that often flow from the test have become increasingly apparent. From 1986 through 2005, one million men received surgery, radiation therapy or both who would not have been treated without a P.S.A. test, according to the task force. Among them, at least 5,000 died soon after surgery and 10,000 to 70,000 suffered serious complications. Half had persistent blood in their semen, and 200,000 to 300,000 suffered impotence, incontinence or both. As a result of these complications, the man who developed the test, Dr. Richard J. Ablin, has called its widespread use a “public health disaster.”
One in six men in the United States will eventually be found to have prostate cancer, making it the second most common form of cancer in men after skin cancer. An estimated 217,730 men received the diagnosis last year, and 32,050 died. The disease is rare before age 50, and most deaths occur after age 75.
Not knowing what is going on with one’s prostate may be the best course, since few men live happily with the knowledge that one of their organs is cancerous. Autopsy studies show that a third of men ages 40 to 60 have prostate cancer, a share that grows to three-fourths after age 85.
P.S.A. testing is most common in men over 70, and it is in that group that it is the most dangerous since such men usually have cancerous prostate cells but benefit the least from surgery and radiation. Some doctors treat patients who have high P.S.A. levels with drugs that block male hormones, although there is no convincing evidence that these drugs are helpful in localized prostate cancer and they often result in impotence, breast enlargement and hot flashes.
Of the trials conducted to assess the value of P.S.A. testing, the two largest were conducted in Europe and the United States. Both “demonstrate that if any benefit does exist, it is very small after 10 years,” according to the task force’s draft recommendation statement.
The European trial had 182,000 men from seven countries who either got P.S.A. testing or did not. When measured across all of the men in the study, P.S.A. testing did not cut death rates in nine years of follow-up. But in men ages 55 to 69, there was a very slight improvement in mortality. The American trial, with 76,693 men, found that P.S.A. testing did not cut death rates after 10 years.
Dr. Eric Klein of the Cleveland Clinic, an expert in prostate cancer, said he disagreed with the task force’s recommendations. Citing the European trial, he said “I think there’s a substantial amount of evidence from randomized clinical trials that show that among younger men, under 65, screening saves lives.”
The task force’s recommendations only applies to healthy men without symptoms. The group did not consider whether the test is appropriate in men who already have suspicious symptoms or those who have already been treated for the disease. The recommendations will be open to public comment next week before they are finalized.
Recommendations of the task force often determine whether federal health programs like Medicare and private health plans envisioned under the health reform law pay fully for a test. But legislation already requires Medicare to pay for P.S.A. testing no matter what the task force recommends.
Still, the recommendations will most likely be greeted with trepidation by the Obama administration, which has faced charges from Republicans that it supports rationing of health care services, which have been politically effective, regardless of the facts.
After the task force’s recommendation against routine mammograms for women under 50, Health and Human Services Secretary Kathleen Sibelius announced that the government would continue to pay for the test for women in their 40s. On Thursday, the administration announced with great fanfare that as a result of the health reform law, more people with Medicare were getting free preventive services like mammograms.
Dr. Michael Rawlins, chairman of the National Institute for Health and Clinical Excellence in Britain, said he was given a P.S.A. test several years ago without his knowledge. He then had a biopsy, which turned out to be negative. But if cancer had been detected, he would have faced an awful choice, he said: “Would I want to have it removed, or would I have gone for watchful waiting with all the anxieties of that?” He said he no longer gets the test.
But Dan Zenka, a spokesman for the Prostate Cancer Foundation, said a high P.S.A. test result eventually led him to have his prostate removed, a procedure that led to the discovery that cancer had spread to his lymph nodes. His organization supports widespread P.S.A. testing. “I can tell you it saved my life,” he said.
Considering When It Might Be Best Not to Know About Cancer
By Gina Kolata : NY Times : October 29, 2011
After decades in which cancer screening was promoted as an unmitigated good, as the best — perhaps only — way for people to protect themselves from the ravages of a frightening disease, a pronounced shift is under way.
Now expert groups are proposing less screening for prostate, breast and cervical cancer and have emphasized that screening comes with harms as well as benefits.
Two years ago, the influential United States Preventive Services Task Force, which evaluates evidence and publishes screening guidelines, said that women in their 40s do not appear to benefit from mammograms and that women ages 50 to 74 should consider having them every two years instead of every year.
This year the group said the widely used P.S.A. screening test for prostate cancer does not save lives and causes enormous harm. It also concluded that most women should have Pap tests for cervical cancer every three years instead of every year.
What changed?
The answer, for the most part, is that more information became available. New clinical trials were completed, as were analyses of other sorts of medical data. Researchers studied the risks and costs of screening more rigorously than ever before.
Two recent clinical trials of prostate cancer screening cast doubt on whether many lives — or any — are saved. And it said that screening often leads to what can be disabling treatments for men whose cancer otherwise would never have harmed them.
A new analysis of mammography concluded that while mammograms find cancer in 138,000 women each year, as many as 120,000 to 134,000 of those women either have cancers that are already lethal or have cancers that grow so slowly they do not need to be treated.
Cancer experts say they cannot ignore a snowballing body of evidence over the past 10 years showing over and over that while early detection through widespread screening can help in some cases, those cases are small in number for most cancers. At the same time, the studies are more clearly defining screening’s harms.
“Screening is always a double-edged sword,” said Dr. Otis Brawley, the chief medical officer of the American Cancer Society. “We need to be more cautious in our advocacy of these screening tests.”
But these concepts are difficult for many to swallow. Specialists like urologists, radiologists and oncologists, who see patients who are sick and dying from cancer, often resist the idea of doing less screening. General practitioners, who may agree with the new guidelines, worry about getting involved in long conversations with patients trying to explain why they might reconsider having a mammogram every year or a P.S.A. test at all.
Some doctors fear lawsuits if they do not screen and a patient develops a fatal cancer. Patients often say they will take their chances with screening’s harms if a test can save their lives.
And comments like Dr. Brawley’s give rise to other questions as well. Is all this happening now because of worries over costs? And in any case, is all this simply an academic argument, since most doctors, faced with real patients, still suggest frequent screening and their patients agree?
The answer, cancer experts say, is, to a certain extent, all of the above. But, they say, there does seem to be a change in the air. Researchers used to be afraid to even broach the subject of screening’s harms.
“It was the third rail,” said Dr. H. Gilbert Welch of Dartmouth Medical School. “We were afraid to say exactly what we thought for fear of seeming too crazy.” It was easy to get financing to study the benefits of screening, he added, but a study that looked at harms was “too far out of the culture.”
Not now, he said.
And with that change has come a new look at screening.
“No longer is it just, Can you find the cancer?” Dr. Brawley said. “Now it is, Can you find the cancer, and does finding the cancer lead to a decrease in the mortality rate?”
Then there is the new emphasis on cost.
The current issue of The New England Journal of Medicine, for example, has an article by two prostate cancer specialists who note that one recent study concludes that $5.2 million must be spent on screening to prevent one prostate cancer death. And, add the authors, Dr. Allan S. Brett of the University of South Carolina School of Medicine and Richard J. Ablin of the University of Arizona, that figure is not inclusive. The true cost is undoubtedly even greater.
“We believe that the current P.S.A.-based screening paradigm does not compare favorably with competing health care priorities,” they wrote.
The cost of screening, said Dr. Russell P. Harris, a screening researcher at the University of North Carolina, “is one of the factors that is pushing toward a tipping point.”
But, medical experts note, many people, including doctors, are confused by the changing message, which is understandable.
“You don’t turn decades of thought around immediately,” said Dr. Timothy J. Wilt, a task force member from the University of Minnesota.
In part, doctors and patients are stuck in a sort of cancer time warp. The disease was defined in 1845 by a German doctor, Rudolf Virchow, who looked attumors taken at autopsy and said cancer is an uncontrolled growth that spreads and kills. But, of course, he was looking only at cancers that killed. He never saw the others.
“Now we are backing away from that,” Dr. Brawley said. In recent years, researchers have found that many, if not most, cancers are indolent. They grow very slowly or stop growing altogether. Some even regress and do not need to be treated — they are harmless.
“We are going from an 1845 definition of cancer to a 21st-century definition of cancer,” Dr. Brawley said.
Dr. Brawley, too, noticed that more people are starting to understand the limitations of screening, and its risks.
Change, though, has been slow in the face of intense promotion of screening by medical practices, hospitals and advocacy groups and years of misunderstandings about screening’s benefits and risks.
“You’ve got all this positive stuff” about screening, Dr. Brawley said. “And you have been taught since you were on your mother’s knee that the way to deal with cancer is to find it early and to cut it out.”
Yet he is optimistic.
“I think people are actually starting to understand that we need to be a little more rigorous in what we accept about screening,” Dr. Brawley said. “I do sense there is some movement there.”
The Screening Dilemma
By Kate Pickert : Time Magazine : June 02, 2011
In the mid–19th century, a german pathologist named Rudolf Virchow discovered that leukemia was caused by the rapid multiplication of abnormal white blood cells. Just like that, with some autopsy samples and a light microscope, Virchow defined cancer — a process in which healthy cells mutate and then reproduce. Before this revelation and for many decades after it, cancerous tumors were found and cut out only when they became visible or palpable. But Virchow's notion that cancer cells start out normal and then go rogue laid a foundation for modern medicine's approach to the disease: early detection.
These days, we no longer have to wait for tumors to make themselves evident. We don't even have to wait for symptoms. Now doctors look for abnormal cells in healthy people, hoping to catch and remove them before they cause sickness, a strategy that has had remarkable results. Along with treatment advances, mammography has reduced the U.S. breast-cancer mortality rate by some 30% since 1989. Pap smears have helped lower the cervical-cancer mortality rate by 60% since 1975. The rate of death from colorectal cancer is also steadily dropping, thanks largely to screening.
It seems that we should be better off finding all cancer early. But this logic may be flawed. Virchow never imagined that modern medicine would have the tools to find tiny cancers at such early stages. The field now includes highly sophisticated blood tests, ultrasound, computed tomography (CT), X-ray, magnetic resonance imaging (MRI) and fine-needle biopsy. Paradoxically, we've become so adept at finding abnormal cells early that there are more cancer patients than ever before. About 4% of the U.S. population are "cancer survivors." "If we had a 100% sensitive test that could pick up everything a pathologist would call cancer, it's conceivable that most of us, if not all of us, would be found to have cancer," says Dr. Barnett Kramer, a medical oncologist and former associate director for disease prevention for the National Institutes of Health (NIH).
"One of the problems is what our definition of cancer is," says Dr. Otis Brawley, chief medical officer of the American Cancer Society (ACS). "Through all the iterations in science, all the advancements in imaging, in understanding diagnostics, in understanding how to do biopsies, we still use Virchow's definition of cancer."
Happily, we don't also use his definition of how the disease progresses. Virchow believed all cancers would eventually spread and lead to death. Yet as scientists have learned how to detect and treat cancer earlier, they have also learned that some cancers never cause any sickness at all. In rare cases, certain cancers can even disappear without treatment. "Early diagnosis has changed the face of what it means to have cancer," says Dr. H. Gilbert Welch, a clinical epidemiologist, cancer-screening researcher and internist at the Veterans Administration Medical Center in White River Junction, Vt. The problem, he says, is that "there are really bad cancers and there are really innocuous ones that never go anywhere, and we're not good at sorting them out."
So we continue to look for more cancers early and treat nearly everything we find as though it would be fatal not to. Patients don't complain. Why would they? Even though the U.S. has so many effective treatment options available — the best in the world, in fact — cancer kills some 600,000 Americans every year. Countermeasures like screening that can be administered in a controlled manner seem like antidotes not only to cancer but also to the disease's inherent unpredictability.
But looking for signs of illness in seemingly healthy people is complicated. Cancer screening is truly effective only if the growths found would eventually cause sickness and if finding those growths earlier increases the efficacy of treatment. Absent these two conditions, finding cancer via screening is what's known as "overdiagnosis," which is guaranteed to happen when screening is performed population-wide. Overdiagnosis causes harm ranging from unnecessary worry to death in rare instances. Says Welch, a professor at Dartmouth Medical School and the lead author of a new book titled Overdiagnosed: "Theoretically, we could spend every day looking for early signs of disease. And we're getting closer and closer to that."
Do No Harm, Unless ...
even in cases in which cancer screening has clearly saved lives, its precise use is controversial. With breast cancer, a debate rages over when women with no risk factors should begin mammography. In 2009 the U.S. Preventive Services Task Force (USPSTF), an independent government body, advised that women get routine mammograms every other year beginning at age 50. Previously, the group had said that mammograms should be annual and begin at 40, which the ACS and other advocacy groups still say is best. The USPSTF changed its advice after determining that the collateral damage of annual screening beginning at 40 wasn't worth the payoff.
Here are the odds. To save the life of one woman in her 40s, 1,904 would have to undergo annual screening. Beyond inconvenience and overexposure to radiation, this excess mammography would lead to false positives; psychological stress, including depression; and unnecessary surgery. In addition, much of the abnormal cell growth detected in women in their 40s could have been detected in their 50s with no adverse effects from the delay.
Not surprisingly, many women railed against the new USPSTF guidelines. Understanding a statistic is one thing. Accepting even the slim chance that you could die of a treatable disease to spare others unnecessary harm is less clear-cut. No woman cares about collateral damage when her life could be at stake.
Colonoscopy, the examination of the colon from within to look for cancer and precancerous polyps, is an accepted standard of care. Doctors often advise average-risk patients to get a colonoscopy at age 50 and, if nothing suspicious is found, every 10 years after that. (See Dr. Oz, page 50.) Yet this advice is given despite the fact that no long-term randomized trial — the industry standard for amassing bulletproof data — has shown colonoscopy, a highly invasive procedure, to be more effective at saving lives than a simple test looking for blood in fecal material or a sigmoidoscopy, a procedure in which just a portion of the colon is examined. One advantage of colonoscopy is that doctors can screen for cancer and intervene if they suspect it, removing suspicious lesions while the patient is still on the examination table. (The USPSTF says colonoscopy, sigmoidoscopy and the fecal-blood test can all be effective.)
Other kinds of screening, like for prostate cancer, are even more contentious. Multiple scientific trials have proved that the ubiquitous prostate-specific antigen (PSA) test saves very few lives, if any. PSA tests are notoriously unreliable, detecting potential cancers where there are none and returning normal results in some men who have malignancies. The doctor who discovered the existence of PSA, a protein that, when elevated, is sometimes an indication of cancer, has disavowed the test, calling it a "profit-driven public-health disaster."
Of men who undergo routine PSA testing, a staggering 17% are eventually diagnosed with cancer, and most of these are treated with radiation or surgery. At least half experience complications such as erectile dysfunction or incontinence. Much of this is needless suffering, since the vast majority of men diagnosed with prostate cancer will not die of it, even if it is left untreated. In fact, for every 1,000 men ages 55 to 70 who undergo annual PSA tests for 10 years, only one life might be saved, according to Welch, who has conducted extensive study on the topic. Meanwhile, an estimated 150 to 200 will have an unneeded biopsy, and 30 to 100 will undergo radiation treatment or have their prostate removed unnecessarily. Despite its ineffectiveness, some 30 million American men have a PSA test every year, partly because it's the best we have for now and prostate cancer remains a deadly disease, killing about 32,000 men annually in the U.S.
Impotence and urinary dysfunction are awful, but the history of poorly designed cancer screening includes tests with much more dire consequences. In the 1960s, many doctors advised American smokers to get chest X-rays to check for lung cancer, the No. 1 cancer killer in the U.S. In the 1970s, the ACS followed suit, and millions heeded the advice. Yet a decade later, studies showed that Americans who were screened for lung cancer via chest X-ray actually had a slightly higher mortality rate than those who were not screened. The excess deaths were due in part to the risky surgery that patients underwent when something was found.
As recently as the 1980s and '90s, doctors in Japan and Quebec screened babies for neuroblastoma, a cancer of the nerve tissue that's the most common type of cancer in infants. The screening revealed alarmingly high cancer rates. "People thought there was a neuroblastoma epidemic," says the ACS's Brawley. "Kids started getting biopsied and then getting surgery, which means basically being filleted open for an 18-month-old." The result was the same as with lung-cancer screening. Mortality rates were slightly higher among the screened population because of deaths caused by surgery. The screening was discontinued. Doctors, it turned out, couldn't distinguish between fatal neuroblastoma and the far more common kind that simply vanishes over time.
Cascades and Incidentalomas
Dr. Jim Mold did not want a PSA test. A family doctor trained in geriatrics, Mold had published journal articles about the hazards of screening and of medical intervention for men with prostate cancer. So it made sense that even though he was 58, solidly in the risk group for prostate cancer and in his doctor's office for a series of unrelated blood tests, he had chosen to forgo a PSA test. He got one anyway. It had inadvertently been added to his order. He noticed at the last minute but didn't protest.
The results showed Mold's PSA was elevated, which typically leads to a biopsy. But Mold was not typical. He understood the test's limitations. So he reread the medical literature on the subject and consulted his colleagues. He avoided sex and treated himself with antibiotics, both of which would have brought his PSA levels down in the absence of cancer. He had another PSA test. Elevated. So he opted for a biopsy. Cancer. Prostate cancer is often slow-growing, so some patients choose watchful waiting over surgery or radiation.
"I was trying to imagine myself living — hopefully 40 more years — with a cancer growing inside of me," remembers Mold. He knew that surgery or radiation could end his sex life and impair his ability to urinate. He knew studies showed that there was a good chance his cancer would never hurt or kill him. Still, he says, "I couldn't resist." He had his entire prostate removed. "I've done really well, and I'm really grateful that I had it done, but I don't know if it was needed," says Mold, now 62. "They say, 'Well, we can stop at any point.' No, you really can't."
Ironically, when he was a young doctor, Mold was one of the first clinicians to write about "the cascade effect," in which patients enter the health care system for one problem or even routine testing and end up getting shuttled through myriad related or unrelated interventions. This can happen in virtually any area of medicine, but cancer screening is particularly risky territory because healthy people are often caught in the net. "Once you've committed to testing, it makes sense to commit to everything else," Welch says. We all imagine we could be the 1 in 1,000 or 1 in 10,000 whose life could be on the line.
"The most important decision is whether or not to be screened," says Dr. Matt Handley, a family doctor and associate medical director for quality and informatics at Group Health, a Seattle-based health-and-insurance system with a zealous adherence to care based on hard evidence.
The chances of getting caught in a diagnostic cascade are increasing thanks to advanced imaging technology. For colorectal cancer, in addition to screening tests that analyze feces and survey the colon internally, there is now virtual colonoscopy. This screening method uses radiation, via CT, to view the organ from outside the body and reconstruct it digitally. CT colonography, as it is called, has advantages. No sedatives are required, and a patient can skip the part in which a doctor threads a scope and light through the rectum. The procedure is also cheaper than a colonoscopy. Whatever savings colonography might appear to present, however, are far outweighed by the cost of following up on all the abnormalities that can show up in the resulting images. These discoveries are known in the medical field as incidentalomas and are typically harmless. As many as 16% of patients undergoing their first virtual colonoscopy are found to have them. Cue the cascade.
Incidentalomas take up so much time, energy and money that some doctors are questioning whether imaging technology has advanced too far. Some doctors are even ignoring the images of the rest of the abdomen created by a CT colonography. They don't want to look, for fear of what they might find. At the same time, imaging-equipment manufacturers are creating higher-resolution scans, increasing even further the chances that something innocuous could be found.
Dr. G. Scott Gazelle, a radiologist at Massachusetts General Hospital who has a Ph.D. in health policy, points out that higher-resolution CT scans require more radiation. "We're starting to question how good the images need to be," he says. Efforts are under way at many hospitals to reduce radiation dosage, but this follows more than a decade of sharp increases. Radiation exposure is part of the reason the USPSTF says it cannot determine whether CT colonography causes more harm or benefit; it assigned the procedure an I rating for "insufficient evidence."
Incidentalomas have the potential to cause even more upheaval for people who undergo CT to screen for lung cancer. Gazelle says there's no doubt that these scans, while exposing patients to many times the radiation of a chest X-ray, can reduce lung-cancer mortality in smokers and former smokers. (A randomized trial to assess lung-cancer-screening CT is under way.) "The question is, At what cost? And by how much?" he says. In addition to the staggering expense of tracking down all the incidentalomas that are likely to be found — lungs are notoriously full of such strange-looking nodules — the physical risks are high. Three to five percent of people who undergo surgery to cut out pieces of their lungs die from the procedure. "Multiply that by the smokers and former smokers in the U.S. population and you could get tens of thousands of deaths," says Gazelle.
The "Fastest-Increasing" Cancers
In 2010, about 45,000 americans were diagnosed with thyroid cancer. That's about three times the diagnosis rate in 1975. But the mortality rate for the disease was the same. There was no more thyroid cancer than before; doctors were just looking and finding more of it. This means that when it comes to lives saved, thyroid-cancer screening may be doing little or no good. In fact, it's probably mostly causing harm.
A recently launched public-awareness campaign called Check Your Neck identifies the disease as "the fastest-increasing cancer in the U.S." Doctors screen for thyroid cancer by palpating the neck, but most necks are lumpy, and it can be hard to tell by touch whether a thyroid is enlarged. Once there's uncertainty, the cascade can take over. Remarkably, many of us, possibly even most of us, will develop thyroid cancer at some point in our lives, but very few of us will die of it. In a 1985 study, researchers examined the bodies of 101 people who had died of causes other than thyroid cancer and found that a third of them contained cancerous thyroid cells. Because of the sampling method, the researchers knew that they were certainly missing some cases, meaning the percentage was even higher, and yet none of those people were killed by the disease.
Still, the vast majority of people in whom thyroid cancer is diagnosed undergo radiation treatment or have their thyroid removed. The surgery leaves some patients hoarse and all forever dependent on medication. Something similar is happening with melanoma, a skin malignancy that kills about 9,000 Americans every year. Awareness campaigns like Melanoma Monday, sponsored by the American Academy of Dermatology, helped raise the melanoma-diagnosis rate 30% from 1975 to 2007. The mortality rate? Unchanged.
The Business of Screening
Among all the reasons overscreening is taking place, the least discussed — and most disturbing — is money. Back in the 1990s, when Brawley, now of the ACS, was an assistant director of the National Cancer Institute, he visited a large research hospital in Atlanta. There, a marketing expert explained that providing free PSA tests to 1,000 men at a local mall could lead to millions of dollars in subsequent revenue for the hospital. The income would come from biopsies, surgeries, radiation and even urinary-sphincter implants in men who experienced complications. This kind of strategy is common, according to Brawley.
Some health centers and urology practices use giveaways to entice men to get PSA tests. In recent years, men have scooped up tickets to Atlanta Hawks, Buffalo Sabres and Tampa Bay Rays games in exchange for getting tested. A nonprofit national organization called Zero, for "zero prostate cancer," tries to get the word out about the benefits of PSA testing, parking a mobile testing unit outside sporting events and churches. The organization doesn't charge patients for tests but accepts donations from urologists, Big Pharma and Beckman Coulter, a PSA-test manufacturer.
The downstream costs of cancer-screening campaigns like this are enormous. Says Welch: "It may lower costs for an individual patient" if minor surgery to remove a suspicious early growth makes major, long-term cancer treatment unnecessary, "but because there are so many more patients created, that effect is overwhelmed." Doctors sometimes encourage screening in part because they believe it could protect them from liability. In addition, the new Affordable Care Act requires insurers to cover "preventive services" at full cost, meaning most patients will pay nothing out of pocket for procedures like mammograms, PSA tests and colonoscopies. This could drive up screening rates even further.
Welch and Handley are urging change upstream. According to a meta-analysis published in 2009, patients are 20% less likely to undergo PSA testing once they understand the potential harms, benefits and uncertainties of it. The VA offers male patients over 50 a DVD and a booklet titled Is a PSA Test Right for You? The material contains the statement "If you find out you have prostate cancer later in life, you will most likely die with the cancer, but probably not because of it."
Advanced screening methods are putting more of us in a similar situation. Many more of us are finding out we have cancer. But even if we can survive cancer, can we live with it? Says Kramer, formerly of the NIH: "The term cancer is so fearsome, many people can't accept the concept that you don't do anything about it." Combine that fear with the American medical system's seemingly limitless capacity for testing and intervention, and excess is inevitable.
"In the U.S. in particular, we just feel like more is always better," says Diana Miglioretti, a biostatistician and investigator for Group Health who studies cancer screening. "There is an uncomfortableness with ambiguity, so we're always looking for that perfect test to save a life."
Calcium supplements in people with osteoporosis should not be given without concomitant treatment for osteoporosis
In the linked systematic review (doi: 10.1136/bmj.c3691), Bolland and colleagues assessed whether calcium supplements increase the risk of cardiovascular events in people with, or at risk of, osteoporosis. They found that calcium supplements increased the risk of myocardial infarction (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67), but they found no significant difference in the risk of stroke, death, or the composite end point of myocardial infarction, stroke, or sudden death.
The effort spent on detecting and treating osteoporosis is only worthwhile if it translates into a health benefit for patients.The most common argument for detecting and treating osteoporosis is a reduction in bone fractures that are either subtle and progressive (for example, those that cause loss of vertebral height) or overt (for example, fractures of the hip and wrist). Bone mineral density, which is often used as a measure of treatment success, is a surrogate measure for real clinical benefit.
Surrogate measures may be useful in pilot studies but become problematic when they become the goal of treatment. Bone fractures in older people are an important cause of disability,and more than 20% of patients will die within one year of a low trauma hip fracture. Accordingly, a safe and effective treatment that can prevent fractures should reduce mortality if given to a large enough population at sufficient risk.
Calcium supplements, given alone, improve bone mineral density, but they are ineffective in reducing the risk of fractures and might even increase risk, they might increase the risk of cardiovascular events, and they do not reduce mortality. They seem to be unnecessary in adults with an adequate diet.Given the uncertain benefits of calcium supplements, any level of risk is unwarranted.
Why should calcium supplements increase cardiovascular risk? Calcium supplements may improve some conventional cardiovascular risk factors including blood pressure and lipids. Accumulation of calcium in the arterial wall leading to reduced compliance would be expected to take years, but the increased risk of myocardial infarction reported by Bolland and colleagues occurred early after calcium supplementation (median follow-up of 3.6 years).
An alternative possibility is that the increased risk of myocardial infarction is not a true effect. If an intervention changes the rate of vascular events but is not associated with a commensurate change in mortality, the intervention may be changing the presentation rather than the incidence. Flecainide reduces the risk of non-fatal myocardial infarction by about 30% because infarctions are more likely to be fatal before patients reach hospital. Similarly,long term treatment with aspirin seems to modify the presentation of vascular events with no effect on mortality and, possibly, with acceleration of the progression of vascular disease. Although the risk of myocardial infarction seemed to increase substantially (by about 25%) with calcium supplementation this was not accompanied by an increase in mortality. Calcium supplements could simply be causing gastrointestinal symptoms that could be misdiagnosed as cardiac chest pain. However, even if calcium supplements really are safe, a neutral effect on mortality casts doubt on whether they are effective prophylaxis for fractures.
A combination of calcium and vitamin D is commonly used to treat osteoporosis. Vitamin D supplements might reduce the risk of falls, might have important clinical effects on cardiovascular function, do not increase mortality, and may mitigate the trend to excess mortality seen with calcium supplements alone. However, no conclusive data are available to show that current doses of vitamin D supplements with or without calcium supplements reduce the rates of fracture, and meta-analyses found evidence of substantial reporting bias.
Several agents that are, or might be, used to treat osteoporosis do reduce mortality, including bisphosphonates, raloxifene and thiazides. However, biphosphonates and raloxifene were generally given in addition to calcium and vitamin D supplements. Other methods of reducing fractures should also be subject to scientific scrutiny. Reducing falls and bone trauma is, probably,the most effective method of reducing fractures, but if it leads to a sedentary lifestyle it might impair both quality of life and longevity. Exercise might be a good way to increase bone strength, although it also carries risk.
Requiring companies to show before licensing that treatments for chronic diseases such as osteoporosis, diabetes, and hypertension reduce long term disability and death could lead to a cessation of research in these areas. The cost and commercial risk would be too high. However, we do need to know whether treatments are safe, effective, and value for money. Extending the patent life of drugs to that of the copyright on a song (50 years according to the Berne Convention) would have many benefits and few drawbacks if properly managed. Regulators could insist that drugs show benefits on symptoms, disability, and mortality rather than surrogate outcomes, which would give doctors and patients greater certainty about the benefits and risks. Regulators could also insist that more trials examine the added value of new compared with old drugs. Lower prices for innovative drugs could be negotiated.Companies could plan a more comprehensive research program with the knowledge that their income streams were more reliable,although still vulnerable to price competition from other companies and to being superseded by more innovative drugs. There would be fewer impediments to the adoption of innovations on financial grounds and less reason to persist with low cost generic drugs if they are inferior.
In the meantime, on the basis of the limited evidence available,patients with osteoporosis should generally not be treated with calcium supplements, either alone or combined with vitamin D, unless they are also receiving an effective treatment for osteoporosis for a recognised indication. Research on whether such supplements are needed as an adjunct to effective agents is urgently required.
Cite this as: BMJ 2010;341:c3856
In Shift, Cancer Society Has Concerns on Screenings
By Gina Kolata : NY Times Article : October 21, 2009
The American Cancer Society, which has long been a staunch defender of most cancer screening, is now saying that the benefits of detecting many cancers, especially breast and prostate, have been overstated.
It is quietly working on a message, to put on its Web site early next year, to emphasize that screening for breast and prostate cancer and certain other cancers can come with a real risk of overtreating many small cancers while missing cancers that are deadly.
“We don’t want people to panic,” said Dr. Otis Brawley, chief medical officer of the cancer society. “But I’m admitting that American medicine has overpromised when it comes to screening. The advantages to screening have been exaggerated.”
Prostate cancer screening has long been problematic. The cancer society, which with more than two million volunteers is one of the nation’s largest voluntary health agencies, does not advocate testing for all men. And many researchers point out that the PSA prostate cancer screening test has not been shown to prevent prostate cancer deaths.
There has been much less public debate about mammograms. Studies from the 1960s to the 1980s found that they reduced the death rate from breast cancer by up to 20 percent.
The cancer society’s decision to reconsider its message about the risks as well as potential benefits of screening was spurred in part by an analysis published Wednesday in The Journal of the American Medical Association, Dr. Brawley said.
In it, researchers report a 40 percent increase in breast cancer diagnoses and a near doubling of early stage cancers, but just a 10 percent decline in cancers that have spread beyond the breast to the lymph nodes or elsewhere in the body. With prostate cancer, the situation is similar, the researchers report.
If breast and prostate cancer screening really fulfilled their promise, the researchers note, cancers that once were found late, when they were often incurable, would now be found early, when they could be cured. A large increase in early cancers would be balanced by a commensurate decline in late-stage cancers. That is what happened with screening for colon and cervical cancers. But not with breast and prostate cancer.
Still, the researchers and others say, they do not think all screening will — or should — go away. Instead, they say that when people make a decision about being screened, they should understand what is known about the risks and benefits.
For now, those risks are not emphasized in the cancer society’s mammogram message which states that a mammogram is “one of the best things a woman can do to protect her health.”
Dr. Brawley says mammograms can prevent some cancer deaths. However, he says, “If a woman says, ‘I don’t want it,’ I would not think badly of her but I would like her to get it.”
But some, like Colin Begg, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York, worry that the increased discussion of screening’s risks is going to confuse the public and make people turn away from screening, mammography in particular.
“I am concerned that the complex view of a changing landscape will be distilled by the public into yet another ‘screening does not work’ headline,” Dr. Begg said. “The fact that population screening is no panacea does not mean that it is useless,” he added.
The new analysis — by Dr. Laura Esserman, a professor of surgery and radiology at the University of California, San Francisco, and director of the Carol Frank Buck Breast Care Center there, and Dr. Ian Thompson, professor and chairman of the department of urology at The University of Texas Health Science Center, San Antonio — finds that prostate cancer screening and breast cancer screening are not so different.
Both have a problem that runs counter to everything people have been told about cancer: They are finding cancers that do not need to be found because they would never spread and kill or even be noticed if left alone. That has led to a huge increase in cancer diagnoses because, without screening, those innocuous cancers would go undetected.
At the same time, both screening tests are not making much of a dent in the number of cancers that are deadly. That may be because many lethal breast cancers grow so fast they spring up between mammograms. And the deadly prostate ones have already spread at the time of cancer screening. The dilemma for breast and prostate screening is that it is not usually clear which tumors need aggressive treatment and which can be left alone. And one reason that is not clear, some say, is that studying it has not been much of a priority.
“The issue here is, as we look at cancer medicine over the last 35 or 40 years, we have always worked to treat cancer or to find cancer early,” Dr. Brawley said. “And we never sat back and actually thought, ‘Are we treating the cancers that need to be treated?’ ”
The very idea that some cancers are not dangerous and some might actually go away on their own can be hard to swallow, researchers say.
“It is so counterintuitive that it raises debate every time it comes up and every time it has been observed,” said Dr. Barnett Kramer, associate director for disease prevention at the National Institutes of Health.
It was first raised as a theoretical possibility in the 1970s, Dr. Kramer said. Then it was documented in a rare pediatric cancer, but was dismissed as something peculiar to that cancer. Then it was discovered in common cancers as well, but it is still not always accepted or appreciated, he said.
But finding those insignificant cancers is the reason the breast and prostate cancer rates soared when screening was introduced, Dr. Kramer said. And those cancers, he said, are the reason screening has the problem called overdiagnosis — labeling innocuous tumors cancer and treating them as though they could be lethal when in fact they are not dangerous.
“Overdiagnosis is pure, unadulterated harm,” he said.
Dr. Peter Albertsen, chief and program director of the urology division at the University of Connecticut Health Center, said that had not been an easy message to get across. “Politically, it’s almost unacceptable,” Dr. Albertsen said. “If you question overdiagnosis in breast cancer, you are against women. If you question overdiagnosis in prostate cancer, you are against men.”
Dr. Esserman hopes that as research continues on how to advance beyond screening, distinguishing innocuous tumors from dangerous ones, people will be more realistic about what screening can do.
“Someone may say, ‘I don’t want to be screened’ ” she said. “Another person may say, ‘Of course I want to be screened.’ Just like everything in medicine, there is no free lunch. For every intervention, there are complications and problems.”
Extra Vitamin E: No Benefit, Maybe Harm
By Jane E. Brody : NY Times Article : March 24, 2009
About three decades ago at a scientific conference on aging, just about every presenter was taking vitamin E, a nutrient with antioxidant properties that, it was thought, would slow the cellular ravages of age.
In subsequent years, many reports from observational and case studies suggested that vitamin E in daily doses far greater than recommended could help to stave off heart disease and stroke, various common cancers, dementia and Alzheimer’s disease, cataracts and macular degeneration, respiratory tract infections and a host of other serious and sometimes fatal health problems.
The logic was that an antioxidant like vitamin E protects cells from the damaging effects of free radicals, which are byproducts of metabolism and exposure to cell-damaging agents like sunlight, radiation and chemotherapy.
Ever hopeful for a magic elixir, millions of health-conscious Americans began self-dosing with amounts of vitamin E dozens of times greater than the recommended daily intake for this fat-soluble nutrient.
If only all those hopeful forecasts had turned out to be true. Just as a well-designed clinical trial disproved the notion that postmenopausal hormones could keep women heart-healthy, controlled clinical trials of vitamin E have found this supplement wanting, as well. The same is true of another antioxidant, vitamin C.
Too Much of a Good Thing
Recent studies have even suggested that at the high doses many people consume, vitamin E could be hazardous. In November 2004, the American Heart Association warned that while the small amounts of vitamin E found in multivitamins and foods were not harmful, taking 400 International Units a day or more could increase the risk of death. The highest recommended dietary allowance for vitamin E is 28.5 IU, for women who are breast-feeding.
No one knows whether other antioxidants, taken as supplements or as concentrates in gourmet beverages, will meet a similar fate, because they have not been rigorously studied. And given the length, cost and difficulty of conducting the needed studies, chances are that these other antioxidants will never be properly investigated. So you may never know whether spending a fortune on pomegranate juice or the like is worth it.
Some vitamin E enthusiasts object that the clinical studies used what they consider the wrong form of the vitamin, saying that each of the vitamin’s eight forms has its own biological activity. But the kind of vitamin E used in most studies, alpha-tocopherol, is the most active form in humans, according to the National Institutes of Health’s Office of Dietary Supplements.
Here, then, is what we now know about vitamin E from recent randomized, controlled clinical trials, the gold standard of research if the right questions were investigated.
Cardiovascular disease. An early hint of no benefit to the heart came from a 2001 University of Pennsylvania study of 30 healthy men, which found that at doses of 200 to 2,000 I.U.’s, vitamin E did not prevent oxidation of blood fats that can damage arteries. Four years later, the Heart Outcomes Prevention Evaluation trials, which looked at nearly 10,000 patients 55 and older with vascular disease or diabetes, found no heart benefit from taking 400 I.U.’s of vitamin E daily for an average of seven years. In fact, those taking the vitamin were more likely to develop heart failure, which prompted the heart association warning.
A few months later came a report on healthy women. The Women’s Health Study, of nearly 40,000 women 45 and older who were followed for an average of 10 years, found no overall benefit in taking 600 I.U.’s of vitamin E every other day for major cardiovascular events (heart attacks and stroke) or total mortality. There was, however, a 24 percent reduction in cardiovascular deaths.
A fresh report on men was released last November. In it, the Physicians’ Health Study, 14,641 men 50 and older were followed for up to eight years, it was found that 400 I.U.’s of vitamin E every other day had no effect on the incidence of major cardiovascular events, including cardiovascular deaths.
The bottom line of all these reports was that supplements of vitamin E could not be relied upon to protect against heart disease and stroke.
Cancer. The Heart Outcomes trials also looked at cancer and found no differences in cancer incidence or deaths during the seven-year follow-up that could be attributed to vitamin E.
Likewise, the Women’s Health Study found no significant effect of the vitamin on total cancer incidence or cancers of the breast, lung or colon, nor any effect on cancer deaths.
Still, hope lingered that vitamin E alone or in combination with the mineral selenium or vitamin C would protect men against prostate cancer. No such luck. In the Jan. 7 issue of The Journal of the American Medical Association, two major reports seemed to have offered the final word on this question.
The Select trial (an acronym for the Selenium and Vitamin E Cancer Prevention Trial) followed 35,533 men from 427 locations in the United States, Canada and Puerto Rico for more than five years. It found no benefit, but did find a “statistically nonsignificant increased risk of prostate cancer” in the group taking 400 I.U.’s a day of vitamin E. Selenium alone offered no benefit, and neither did selenium combined with vitamin E.
The second study, a continuation of the Physicians’ Health Study, found that among male doctors who took 400 I.U.’s of vitamin E every other day and 500 milligrams of vitamin C every day, there was no decreased risk of developing prostate cancer or cancer in general.
For lung cancer, a 2007 study financed by the National Cancer Institute found that smokers who took vitamin E supplements had a somewhat higher risk of developing the disease.
Other diseases. An independent review of studies by the Cochrane Collaboration published last year found no reliable evidence for the ability of vitamin E to prevent or treat Alzheimer’s disease or mild cognitive impairment, not even at doses of 2,000 I.U.’s a day.
And while vitamin E is part of complex formulations that have been found to slow the progression of macular degeneration, no one can say if the vitamin has played any role in the benefits seen with these products.
There are possible risks as well, since vitamin E diminishes the clotting tendency of blood and may result in ugly bruises from small bumps.
Simply put, there is no quick fix. The best chance for leading a long and healthy life comes not from any pill or potion but from pursuing a wholesome lifestyle. That means following a nutrient-filled but calorically moderate diet rich in vegetables, fruits and whole grains (many are good sources of vitamin E); not smoking; exercising regularly; maintaining a normal body weight; and driving and riding safely.
Here’s to your health.
In Shift to Digital, More Repeat Mammograms
By Denise Grady : NY Times Article : April 10, 2008
It is a phone call that women dread. Something is not quite right on the mammogram: come back for another one. But don’t worry, the script goes, most repeat tests wind up normal.
Still, most women know someone who has breast cancer, and even the calmest, most rational minds may think the worst when summoned back to the clinic.
At many centers, these nerve-racking calls are on the rise, at least temporarily — the price of progress as more and more radiologists switch from traditional X-ray film to digital mammograms, in which the X-ray images are displayed on a computer monitor.
Problems can arise during the transition period, while doctors learn to interpret digital mammograms and compare them to patients’ previous X-ray films. Comparing past and present to look for changes is an essential part of reading mammograms. But the digital and film versions can sometimes be hard to reconcile, and radiologists who are retraining their eyes and minds may be more likely to play it safe by requesting additional X-rays — and sometimes ultrasound exams and even biopsies — in women who turn out not to have breast cancer.
Digital is growing fast. In the United States, 32 percent of mammography clinics now have at least one digital machine, up from only 10 percent two years ago. Eventually, film will be phased out.
The rush to digital is occurring in part because for certain women — younger ones and others with dense breast tissue — it is better than film at finding tumors. Digital is especially good at picking up tiny calcium deposits, or calcifications, which are sometimes — but by no means always — a sign of cancer. In the long run, radiologists say, digital technology will make mammograms more accurate for many women.
There have been no studies yet to measure what happens during the transition period, but many radiologists say they do find themselves calling more women back. About 35.8 million mammograms a year are done in the United States, including those for screening and follow-ups for problems. The National Cancer Institute recommends mammograms every year or two for most women over 40 (women at high risk may be advised to start earlier). Mammography is not perfect — it can miss tumors — but even its critics say it has helped to lower death rates from breast cancer, which is the second leading cause of cancer deaths in women, after lung cancer.
There are about 178,000 new cases of breast cancer each year in the United States, and 40,000 deaths.
Of 10 radiologists interviewed for this article, eight said that during the transition from film to digital, recall rates went up in women who were ultimately found to have nothing wrong. Normally a recall rate of 10 percent or less is considered desirable. But during the transition period at their clinics, the doctors estimated that callbacks of women who turned out to be healthy increased by a few percentage points to as many as 10. Only one radiologist reported no problems: Dr. Etta D. Pisano, a professor of radiology and biomedical engineering at the University of North Carolina.
“I don’t believe it,” Dr. Pisano said. “I question that there’s a problem with the transition.”
But Dr. Mary Mahoney, a professor of radiology and the director of breast imaging at the University of Cincinnati Medical Center, said, “I am living through the pain of this transition period on a daily basis.”
Dr. Mahoney’s center recently opened an entirely digital clinic for breast cancer screening.
“Our whole group is kind of pulling our hair out some days,” she said. “You struggle and you struggle. It’s just so much harder. These are really experienced, qualified radiologists who are wringing their hands. It’s where the increase in callbacks and biopsies is coming into play. It happens every day. Many times we’re able to bring the woman back, do additional views and feel comfortable we can follow that area.”
Regarding the higher callback rates, Dr. Mahoney said: “I know it’s not a small thing, the anxiety. Patients are practically in tears because they’re so worried. But I think in the long run it’s going to be to everybody’s benefit.”
Dr. Margarita Zuley, the director of breast imaging at Magee-Women’s Hospital at the University of Pittsburgh Medical Center, said it could take six months to a year to learn to interpret the new images.
Lecturing in Manhattan recently about the transition to digital, Dr. Zuley told an audience of radiologists: “When you first start out, you may feel a little anxious and recall more patients because everything looks like a cancer to you. It’s O.K. Just bring the patients back. It’s part of the learning curve.”
Regarding higher recall rates during the transition, Dr. Zuley said: “Everybody sort of knows it, but it’s anecdotal. There are no numbers.”
Meanwhile, patients or their insurers are paying for the extra tests. Fees for mammograms vary around the country. A clinic in Manhattan recently billed an insurer $387 for a digital mammogram and then $336 for extra images of one breast — needed because of confusion between the old films and the new digital pictures — and was paid about half of those fees. Fees for film-based mammograms are usually $45 to $120 less.
Nancy Liber, a radiologic technologist at Dr. Mahoney’s center, was called back by her own colleagues at the center after her mammogram last month.
“I thought exactly what every woman does,” Ms. Liber said. “Immediately you panic and think, ‘Oh my gosh, what if something is really wrong?’ ”
She found herself worrying about what would happen if she became ill and unable to take care of her children. She did not even tell her husband what had happened until after the second test, which turned out normal. The concerns were due entirely to the difference between film and digital images. Despite the stressful experience, Ms. Liber said that from what she had seen in her work, digital mammograms were the way to go.
“The inconvenience it may cause is worth it,” she said. But, she added, “I definitely know what these women are going through.”
Radiologists say one of digital’s advantages is that it lets them adjust features like contrast and magnification, and see things that were blurry or maybe even invisible on film. In the long run, doctors say, the increased clarity of digital mammograms may lead to fewer callbacks of healthy women — but it takes time to learn the ropes.
Dr. Constance D. Lehman, the director of breast imaging and a professor of radiology at the University of Washington, said she was not sure whether more women were called back during the transition. But describing the two technologies, she said, “In some areas it’s like comparing apples and oranges.”
When looking at a woman’s first digital image, Dr. Lehman said, radiologists must ask themselves whether a seeming change in the breast is truly new, or was it there all along but just not visible with earlier techniques.
Once a woman has had enough digital mammograms, the comparisons should be easier, radiologists say. But the first few may raise questions because when radiologists compare, they often go back to images from two or three years before. And in some clinics that have a mixture of film and digital machines, if a woman is switched between the two types from year to year, ambiguities may crop up again and again.
Many women do not know the difference between film and digital, or notice which is being used, and clinics may or may not inform them of potential problems during the changeover.
Digital mammography got a boost from a large study in 2005 that showed it was better than film at finding tumors in women under 50, or women of any age who had dense breasts, meaning a lot of glandular and connective tissue in proportion to fat.
A buzz grew around digital after the study. Some radiologists use the technology as a selling point, and others feel they must follow suit. Now there is such a demand for digital machines that there is a six-month wait for certain types, Dr. Zuley said, even though they cost $350,000 to $600,000, about three to five times as much as units that use film.
Dr. Leonard M. Glassman, who practices at Washington Radiology Associates, said that his practice in the Washington, D.C., area, which performs 85,000 mammograms a year, converted to digital about two years ago.
“There’s an increase in the rate of things you think are abnormal for about three months, and then you get used to it,” Dr. Glassman said. “You take more extra pictures, of things that six months later you would dismiss. It happened probably 5 to 10 percent of the time right at the beginning, so it’s a significant amount, and then it tails off.”
When questions first arise, Dr. Glassman said, he does not warn women that the imaging may be the culprit because he cannot be sure what the problem is until he sees the second set of X-rays.
“At the end I tell patients, ‘You were a victim of technology,’ ” he said. “They give me a blank stare. I say: ‘Your last one was film; this one was digital. They look different, and we just didn’t know that.’ ”
Diabetes Study Partially Halted After Deaths
By Gina Kolata : NY Times Article : February 8, 2008
For decades, researchers believed that if people with diabetes lowered their blood sugar to normal levels, they would no longer be at high risk of dying from heart disease. But a major federal study of more than 10,000 middle-aged and older people with Type 2 diabetes has found that lowering blood sugar actually increased their risk of death, researchers reported Wednesday.
The researchers announced that they were abruptly halting that part of the study, whose surprising results call into question how the disease, which affects 21 million Americans, should be managed.
The study’s investigators emphasized that patients should still consult with their doctors before considering changing their medications.
Among the study participants who were randomly assigned to get their blood sugar levels to nearly normal, there were 54 more deaths than in the group whose levels were less rigidly controlled. The patients were in the study for an average of four years when investigators called a halt to the intensive blood sugar lowering and put all of them on the less intense regimen.
The results do not mean blood sugar is meaningless. Lowered blood sugar can protect against kidney disease, blindness and amputations, but the findings inject an element of uncertainty into what has been dogma — that the lower the blood sugar the better and that lowering blood sugar levels to normal saves lives.
Medical experts were stunned.
“It’s confusing and disturbing that this happened,” said Dr. James Dove, president of the American College of Cardiology. “For 50 years, we’ve talked about getting blood sugar very low. Everything in the literature would suggest this is the right thing to do,” he added.
Dr. Irl Hirsch, a diabetes researcher at the University of Washington, said the study’s results would be hard to explain to some patients who have spent years and made an enormous effort, through diet and medication, getting and keeping their blood sugar down. They will not want to relax their vigilance, he said.
“It will be similar to what many women felt when they heard the news about estrogen,” Dr. Hirsch said. “Telling these patients to get their blood sugar up will be very difficult.”
Dr. Hirsch added that organizations like the American Diabetes Association would be in a quandary. Its guidelines call for blood sugar targets as close to normal as possible.
And some insurance companies pay doctors extra if their diabetic patients get their levels very low.
The low-blood sugar hypothesis was so entrenched that when the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases proposed the study in the 1990s, they explained that it would be ethical. Even though most people assumed that lower blood sugar was better, no one had rigorously tested the idea. So the study would ask if very low blood sugar levels in people with Type 2 diabetes — the form that affects 95 percent of people with the disease — would protect against heart disease and save lives.
Some said that the study, even if ethical, would be impossible. They doubted that participants — whose average age was 62, who had had diabetes for about 10 years, who had higher than average blood sugar levels, and who also had heart disease or had other conditions, like high blood pressure and high cholesterol, that placed them at additional risk of heart disease — would ever achieve such low blood sugar levels.
Study patients were randomly assigned to one of three types of treatments: one comparing intensity of blood sugar control; another comparing intensity of cholesterol control; and the third comparing intensity of blood pressure control. The cholesterol and blood pressure parts of the study are continuing.
Dr. John Buse, the vice-chairman of the study’s steering committee and the president of medicine and science at the American Diabetes Association, described what was required to get blood sugar levels low, as measured by a protein, hemoglobin A1C, which was supposed to be at 6 percent or less.
“Many were taking four or five shots of insulin a day,” he said. “Some were using insulin pumps. Some were monitoring their blood sugar seven or eight times a day.”
They also took pills to lower their blood sugar, in addition to the pills they took for other medical conditions and to lower their blood pressure and cholesterol. They also came to a medical clinic every two months and had frequent telephone conversations with clinic staff.
Those assigned to the less stringent blood sugar control, an A1C level of 7.0 to 7.9 percent, had an easier time of it. They measured their blood sugar once or twice a day, went to the clinic every four months and took fewer drugs or lower doses.
So it was quite a surprise when the patients who had worked so hard to get their blood sugar low had a significantly higher death rate, the study investigators said.
The researchers asked whether there were any drugs or drug combinations that might have been to blame. They found none, said Dr. Denise G. Simons-Morton, a project officer for the study at the National Heart, Lung and Blood Institute. Even the drug Avandia, suspected of increasing the risk of heart attacks in diabetes, did not appear to contribute to the increased death rate.
Nor was there an unusual cause of death in the intensively treated group, Dr. Simons-Morton said. Most of the deaths in both groups were from heart attacks, she added.
For now, the reasons for the higher death rate are up for speculation. Clearly, people without diabetes are different from people who have diabetes and get their blood sugar low.
It might be that patients suffered unintended consequences from taking so many drugs, which might interact in unexpected ways, said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.
Or it may be that participants reduced their blood sugar too fast, Dr. Hirsch said. Years ago, researchers discovered that lowering blood sugar very quickly in diabetes could actually worsen blood vessel disease in the eyes, he said. But reducing levels more slowly protected those blood vessels.
And there are troubling questions about what the study means for people who are younger and who do not have cardiovascular disease. Should they forgo the low blood sugar targets?
No one knows.
Other medical experts say that they will be discussing and debating the results for some time.
“It is a great study and very well run,” Dr. Dove said. “And it certainly had the right principles behind it.”
But maybe, he said, “there may be some scientific principles that don’t hold water in a diabetic population.”
Diabetes Health Goes Beyond Blood Sugar
By Tara Parker-Pope : NY Times Article : February 8, 2008
The startling findings of a major federal study on the effects of lowering blood sugar are unlikely to change the way most people with Type 2 diabetes manage their illness, doctors said Thursday.
The study, announced Wednesday, showed that an intensive program to lower blood sugar actually increased risk of death. The findings were so surprising that the study was stopped early, and they seemed to undercut the accepted wisdom that people with diabetes should do everything possible to get their blood sugar down to normal.
But the methods used in the study, called Accord (for Action to Control Cardiovascular Risk in Diabetes), bear little resemblance to the techniques most doctors and patients use to manage blood sugar levels. And the patients in the study were typically far sicker than many people with diabetes today.
“The intensity of what we did is done virtually nowhere on the planet,” said Dr. John Buse, vice chairman of the study’s steering committee and the president of medicine and science at the American Diabetes Association. “It’s far beyond what’s common in clinical practice.” Dr. Buse called the study’s regimen to lower blood sugar a “brutal program.”
Still, doctors are likely to reconsider their emphasis on lowering blood sugar at all costs, because it is becoming clear that other factors influence the overall health of patients with diabetes.
The New England Journal of Medicine published a study this week showing that a three-pronged approach of managing sugar, blood pressure and cholesterol — combined with low doses of aspirin — prolonged the lives of people with diabetes. The patients who did best in that study did not reach the nearly normal sugar levels that were the aim of the Accord study. Instead, their levels were just slightly higher than normal.
In the Accord study, the group of patients who were randomly assigned to lower their blood sugar levels to nearly normal had 54 more deaths than the group whose levels were less rigidly controlled. The patients were in the study for an average of four years when investigators stopped the intense regimen and put all of them on the less intense one.
“When we look at mortality in patients with Type 2 diabetes, it’s not only the blood sugar,” said Dr. Joel Zonszein, director of the Clinical Diabetes Center at Montefiore Medical Center in the Bronx. “What the study shows is that just lowering blood sugar is not protecting you from dying sooner. Blood sugar is important, but so is blood pressure and cholesterol.”
Patients with newly diagnosed diabetes still appear to have much to gain by keeping their blood sugar levels as close to normal as possible through healthful eating and exercise. But patients who have had a heart attack and have other risk factors need not feel guilty if they cannot get their blood sugar to normal levels, Dr. Buse said.
“The most important thing is get your blood pressure controlled, cholesterol controlled, and do a reasonable job on your diabetes, but don’t go wild,” he said. “We are backing away from notion that we always have to push, push, push to get blood sugar lower.”
Today, many patients with diabetes take two or three drugs to manage their blood sugar levels. In the Accord study, many patients took multiple drugs and insulin shots, adhered to strict diets and regularly met with counselors and doctors who monitored them. No single drug treatment was prescribed; doctors used whatever combination of various treatments that appeared to work best in each patients.
The researchers still have to sift through the data on those who died to find out whether there was any pattern that might help explain why patients in the intense treatment group fared worse. It may be that they were simply sicker to begin with. It may have been the number of drugs they used or the pace at which their blood sugar dropped.
Dr. Buse said one little-discussed issue was the sheer stress of the treatment program itself. He noted that the program demanded a lot of effort from patients but that it was still exceedingly difficult for any of them to achieve the blood sugar levels that had been set for them. Many patients with diabetes feel stressed when they fail to meet blood sugar goals set by their doctors.
“At some level I just wonder if some of them were just overwhelmed by this psychologically,” Dr. Buse said. “Could it be the stress of ‘I’m trying so hard, but I can’t get it done’?”
FDA warns of deadly side effect with imaging drugs
By Matthew Perrone, AP Business Writer | September 9, 2010
Federal health regulators are warning doctors that a class of injectable drugs used in MRI medical imaging scans can cause a rare and sometimes fatal condition in patients with kidney disease.
The Food and Drug Administration said Thursday it is adding its strongest warning label to imaging agents that contain the chemical gadolinium, highlighting the risks when used in patients with kidney problems.
"These label changes are intended to help ensure these drugs are used appropriately," the FDA said in a posting to its website. The warning language will appear in a bolded box at the top of the drugs' labels.
The agency said in a statement that use of the drugs can lead to a rare syndrome that causes hardening of the skin and tissue growth along joints, eyes and internal organs. The ailment, which is sometimes fatal, is called nephrogenic fibrosing dermopathy and has been reported in patients with weakened kidney function.
There is no known treatment for the condition, though kidney transplant appears to slow disease and even reverse it in some cases.
Known as contrast agents, the products are used to improve clarity in medical scans of the heart and other internal organs. The FDA has approved seven such agents since 1988.
While the nephrogenic syndrome has been reported with all seven drugs, the FDA said three have greater risks than the others: Bayer Healthcare's Magnevist, General Electric Healthcare's Omniscan and Covidien's Optimark. The FDA label stresses that these drugs should not be used in patients with kidney disease.
An agency spokeswoman said those three drugs are "chemically more unstable" than the others in the class and "thus more likely to release gadolinium."
Gadolinium is a metal with distinctive magnetic properties that increase its visibility during MRI scans. It is known to be toxic to the liver.
The four other drugs are Prohance and Multihance from Brocco Diagnostics Inc., Bayer's Eovist and Ablavar from Lantheus Medical Imaging.
The new FDA labels for all seven drugs instruct physicians to screen patients for kidney disease before administering the agents. Doctors should also order lab tests for patients who may be at increased risk of reduced kidney function. The FDA said there haven't been any reports of the syndrome in patients with normal kidney function.
There are two non-gadolinium-based imaging agents on the market, though the FDA has approved them only for liver scans.
GE Healthcare said in a statement that the FDA's labeling reinforces physician guidelines that already stress the importance of screening for patients with kidney problems.
The company said MRI contrast agents "continue to be a valuable diagnostic tool with a proven safety record for the overwhelming majority of patients to whom they are prescribed."
Bayer said it will cooperate with regulators and "will make periodic safety reports to the FDA and other regulators."
By Matthew Perrone, AP Business Writer | September 9, 2010
Federal health regulators are warning doctors that a class of injectable drugs used in MRI medical imaging scans can cause a rare and sometimes fatal condition in patients with kidney disease.
The Food and Drug Administration said Thursday it is adding its strongest warning label to imaging agents that contain the chemical gadolinium, highlighting the risks when used in patients with kidney problems.
"These label changes are intended to help ensure these drugs are used appropriately," the FDA said in a posting to its website. The warning language will appear in a bolded box at the top of the drugs' labels.
The agency said in a statement that use of the drugs can lead to a rare syndrome that causes hardening of the skin and tissue growth along joints, eyes and internal organs. The ailment, which is sometimes fatal, is called nephrogenic fibrosing dermopathy and has been reported in patients with weakened kidney function.
There is no known treatment for the condition, though kidney transplant appears to slow disease and even reverse it in some cases.
Known as contrast agents, the products are used to improve clarity in medical scans of the heart and other internal organs. The FDA has approved seven such agents since 1988.
While the nephrogenic syndrome has been reported with all seven drugs, the FDA said three have greater risks than the others: Bayer Healthcare's Magnevist, General Electric Healthcare's Omniscan and Covidien's Optimark. The FDA label stresses that these drugs should not be used in patients with kidney disease.
An agency spokeswoman said those three drugs are "chemically more unstable" than the others in the class and "thus more likely to release gadolinium."
Gadolinium is a metal with distinctive magnetic properties that increase its visibility during MRI scans. It is known to be toxic to the liver.
The four other drugs are Prohance and Multihance from Brocco Diagnostics Inc., Bayer's Eovist and Ablavar from Lantheus Medical Imaging.
The new FDA labels for all seven drugs instruct physicians to screen patients for kidney disease before administering the agents. Doctors should also order lab tests for patients who may be at increased risk of reduced kidney function. The FDA said there haven't been any reports of the syndrome in patients with normal kidney function.
There are two non-gadolinium-based imaging agents on the market, though the FDA has approved them only for liver scans.
GE Healthcare said in a statement that the FDA's labeling reinforces physician guidelines that already stress the importance of screening for patients with kidney problems.
The company said MRI contrast agents "continue to be a valuable diagnostic tool with a proven safety record for the overwhelming majority of patients to whom they are prescribed."
Bayer said it will cooperate with regulators and "will make periodic safety reports to the FDA and other regulators."
Doubt Cast on the ‘Good’ in
‘Good Cholesterol’
By Gina Kolata : NY Times : May 16, 2012
The name alone sounds so encouraging: HDL, the “good cholesterol.” The more of it in your blood, the lower your risk of heart disease. So bringing up HDL levels has got to be good for health.
Or so the theory went.
Now, a new study that makes use of powerful databases of genetic information has found that raising HDL levels may not make any difference to heart disease risk. People who inherit genes that give them naturally higher HDL levels throughout life have no less heart disease than those who inherit genes that give them slightly lower levels. If HDL were protective, those with genes causing higher levels should have had less heart disease.
Researchers not associated with the study, published online Wednesday in The Lancet, found the results compelling and disturbing. Companies are actively developing and testing drugs that raise HDL, although three recent studies of such treatments have failed. And patients with low HDL levels are often told to try to raise them by exercising or dieting or even by taking niacin, which raised HDL but failed to lower heart disease risk in a recent clinical trial.
“I’d say the HDL hypothesis is on the ropes right now,” said Dr. James A. de Lemos, a professor at the University of Texas Southwestern Medical Center, who was not involved in the study.
Dr. Michael Lauer, director of the division of cardiovascular sciences at the National Heart, Lung and Blood Institute, agreed.
“The current study tells us that when it comes to HDL we should seriously consider going back to the drawing board, in this case meaning back to the laboratory,” said Dr. Lauer, who also was not connected to the research. “We need to encourage basic laboratory scientists to figure out where HDL fits in the puzzle — just what exactly is it a marker for.”
But Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, who is helping conduct studies of HDL-raising drugs, said he remained hopeful. HDL is complex, he said, and it is possible that some types of HDL molecules might in fact protect against heart disease.
“I am an optimist,” Dr. Nissen said.
The study’s authors emphasize that they are not questioning the well-documented finding that higher HDL levels are associated with lower heart disease risk. But the relationship may not be causative. Many assumed it was because the association was so strong and consistent. Researchers also had a hypothesis to explain how HDL might work. From studies with mice and with cells grown in the laboratory, they proposed that HDL ferried cholesterol out of arteries where it did not belong.
Now it seems that instead of directly reducing heart disease risk, high HDL levels may be a sign that something else is going on that makes heart disease less likely. To investigate the relationship between HDL and cardiovascular risk, the researchers, led by Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and a geneticist at the Broad Institute of M.I.T. and Harvard, used a method known as Mendelian randomization. It is a study design that has recently become feasible with the advent of quick and lower-cost genetic analyses.
The idea is that people inherit any of a wide variety of genetic variations that determine how much HDL they produce. The result is that people are naturally and randomly assigned by these variations in their inherited genes to make more, or less, HDL, throughout their lives. If HDL reduces the risk of heart disease, then those who make more should be at lower risk.
For purposes of comparison, the researchers also examined inherited variations in 13 genes that determine levels of LDL, the so-called bad cholesterol. It is well known and widely accepted that lowering LDL levels by any means — diet and exercise, statin drugs — reduces risk. Clinical trials with statins established with certainty that reducing LDL levels is protective. So, the researchers asked, did people who inherited gene variations that affected their LDL levels, have correspondingly higher or lower heart disease risk?
The study found, as expected, that gene variations that raise LDL increase risk and those that lower LDL decrease risk. The gene effects often were tiny, altering LDL levels by only a few percent. But the data, involving tens of thousands of people, clearly showed effects on risk.
“That speaks to how powerful LDL is,” Dr. Kathiresan said.
But the HDL story was very different. First the investigators looked at variations in a well-known gene, endothelial lipase, that affects only HDL. About 2.6 percent of the population has a variation in that gene that raises their HDL levels by about 6 points. The investigators looked at 116,000 people, asking if they had the variant and if those who carried the HDL-raising variant had lower risk for heart disease.
“We found absolutely no association between the HDL-boosting variant and risk for heart disease,” Dr. Kathiresan said. “That was very surprising to us.”
Then they looked at a group of 14 gene variants that also affect HDL levels, asking if there was a relationship between these variants and risk for heart disease. The data included genetic data on 53,500 people. Once again, there was no association between having the variants that increased HDL and risk of heart disease.
Dr. Lauer explains what that means with an analogy.
“One might think of a highway accident that causes a massive traffic jam,” he said. “Stewing in the jam many miles away, I might be tempted to strike the sign that says ‘accident ahead,’ but that won’t do any good. The ‘accident-ahead’ sign is not the cause of the traffic jam — the accident is. Analogously, targeting HDL won’t help if it’s merely a sign.”
Dr. Kathiresan said there were many things HDL might indicate. “The number of factors that track with low HDL is a mile long,” he said. “Obesity, being sedentary, smoking, insulin resistance, having small LDL particles, having increased cholesterol in remnant particles, and having increased amounts of coagulation factors in the blood,” he said. “Our hypothesis is that much of the association may be due to these other factors.”
“I often see patients in the clinic with low HDL levels who ask how they can raise it,” Dr. Kathiresan said. “I tell them, ‘It means you are at increased risk, but I don’t know if raising it will affect your risk.’ ”
That often does not go over well, he added. The notion that HDL is protective is so entrenched that the study’s conclusions may prove hard to accept, he and other researchers said.
“When people see numbers in the abnormal range they want to do something about it,” Dr. Kathiresan said. “It is very hard to get across the concept that the safest thing might be to leave people alone.”
‘Good Cholesterol’
By Gina Kolata : NY Times : May 16, 2012
The name alone sounds so encouraging: HDL, the “good cholesterol.” The more of it in your blood, the lower your risk of heart disease. So bringing up HDL levels has got to be good for health.
Or so the theory went.
Now, a new study that makes use of powerful databases of genetic information has found that raising HDL levels may not make any difference to heart disease risk. People who inherit genes that give them naturally higher HDL levels throughout life have no less heart disease than those who inherit genes that give them slightly lower levels. If HDL were protective, those with genes causing higher levels should have had less heart disease.
Researchers not associated with the study, published online Wednesday in The Lancet, found the results compelling and disturbing. Companies are actively developing and testing drugs that raise HDL, although three recent studies of such treatments have failed. And patients with low HDL levels are often told to try to raise them by exercising or dieting or even by taking niacin, which raised HDL but failed to lower heart disease risk in a recent clinical trial.
“I’d say the HDL hypothesis is on the ropes right now,” said Dr. James A. de Lemos, a professor at the University of Texas Southwestern Medical Center, who was not involved in the study.
Dr. Michael Lauer, director of the division of cardiovascular sciences at the National Heart, Lung and Blood Institute, agreed.
“The current study tells us that when it comes to HDL we should seriously consider going back to the drawing board, in this case meaning back to the laboratory,” said Dr. Lauer, who also was not connected to the research. “We need to encourage basic laboratory scientists to figure out where HDL fits in the puzzle — just what exactly is it a marker for.”
But Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, who is helping conduct studies of HDL-raising drugs, said he remained hopeful. HDL is complex, he said, and it is possible that some types of HDL molecules might in fact protect against heart disease.
“I am an optimist,” Dr. Nissen said.
The study’s authors emphasize that they are not questioning the well-documented finding that higher HDL levels are associated with lower heart disease risk. But the relationship may not be causative. Many assumed it was because the association was so strong and consistent. Researchers also had a hypothesis to explain how HDL might work. From studies with mice and with cells grown in the laboratory, they proposed that HDL ferried cholesterol out of arteries where it did not belong.
Now it seems that instead of directly reducing heart disease risk, high HDL levels may be a sign that something else is going on that makes heart disease less likely. To investigate the relationship between HDL and cardiovascular risk, the researchers, led by Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and a geneticist at the Broad Institute of M.I.T. and Harvard, used a method known as Mendelian randomization. It is a study design that has recently become feasible with the advent of quick and lower-cost genetic analyses.
The idea is that people inherit any of a wide variety of genetic variations that determine how much HDL they produce. The result is that people are naturally and randomly assigned by these variations in their inherited genes to make more, or less, HDL, throughout their lives. If HDL reduces the risk of heart disease, then those who make more should be at lower risk.
For purposes of comparison, the researchers also examined inherited variations in 13 genes that determine levels of LDL, the so-called bad cholesterol. It is well known and widely accepted that lowering LDL levels by any means — diet and exercise, statin drugs — reduces risk. Clinical trials with statins established with certainty that reducing LDL levels is protective. So, the researchers asked, did people who inherited gene variations that affected their LDL levels, have correspondingly higher or lower heart disease risk?
The study found, as expected, that gene variations that raise LDL increase risk and those that lower LDL decrease risk. The gene effects often were tiny, altering LDL levels by only a few percent. But the data, involving tens of thousands of people, clearly showed effects on risk.
“That speaks to how powerful LDL is,” Dr. Kathiresan said.
But the HDL story was very different. First the investigators looked at variations in a well-known gene, endothelial lipase, that affects only HDL. About 2.6 percent of the population has a variation in that gene that raises their HDL levels by about 6 points. The investigators looked at 116,000 people, asking if they had the variant and if those who carried the HDL-raising variant had lower risk for heart disease.
“We found absolutely no association between the HDL-boosting variant and risk for heart disease,” Dr. Kathiresan said. “That was very surprising to us.”
Then they looked at a group of 14 gene variants that also affect HDL levels, asking if there was a relationship between these variants and risk for heart disease. The data included genetic data on 53,500 people. Once again, there was no association between having the variants that increased HDL and risk of heart disease.
Dr. Lauer explains what that means with an analogy.
“One might think of a highway accident that causes a massive traffic jam,” he said. “Stewing in the jam many miles away, I might be tempted to strike the sign that says ‘accident ahead,’ but that won’t do any good. The ‘accident-ahead’ sign is not the cause of the traffic jam — the accident is. Analogously, targeting HDL won’t help if it’s merely a sign.”
Dr. Kathiresan said there were many things HDL might indicate. “The number of factors that track with low HDL is a mile long,” he said. “Obesity, being sedentary, smoking, insulin resistance, having small LDL particles, having increased cholesterol in remnant particles, and having increased amounts of coagulation factors in the blood,” he said. “Our hypothesis is that much of the association may be due to these other factors.”
“I often see patients in the clinic with low HDL levels who ask how they can raise it,” Dr. Kathiresan said. “I tell them, ‘It means you are at increased risk, but I don’t know if raising it will affect your risk.’ ”
That often does not go over well, he added. The notion that HDL is protective is so entrenched that the study’s conclusions may prove hard to accept, he and other researchers said.
“When people see numbers in the abnormal range they want to do something about it,” Dr. Kathiresan said. “It is very hard to get across the concept that the safest thing might be to leave people alone.”
