Cautious Optimism for a New Melanoma Treatment

This morning’s news feed delivered some seemingly excellent news for some people with melanoma. At least until now, this form of skin cancer has been considered incurable when metastatic. In the last year, we heard details about the ups and downs of ongoing clinical trials of new drugs to treat the disease.

The Times reports that Roche’s experimental drug prolongs life in patients with metastatic melanoma whose tumors have B-Raf mutations. The new findings, based on a randomized phase III, open-label and industry-sponsored trial, BRIM 3, were first communicated in a press release yesterday. The company indicates that the study met its primary endpoints: Patients taking the experimental pill, RG7204, lived longer, and went longer without disease progression, than those patients in the control arm who received standard chemotherapy (dacarbazine) injections every three weeks.

The new drug – a pill usually given at a dose of 960 milligrams twice daily – goes by several names:

RG7204 (Genentech is a Roche subsidiary)

PLX4032 (Plexxikon has a partnership with Roche to commercialize and develop PLX4032)

RO5185426 (as listed at ClinicalTrials.gov and the NCI thesaurus)

Since the Phase III study opened in January 2010, investigators recruited patients at numerous medical centers worldwide. According to the Roche press release, nearly subjects were randomized to receive either the experimental pill (960 mg) twice daily or dacarbazine (1000 mg/m2) by intravenous every 3 weeks. Patients continued on their assigned drug until the disease progressed or they experienced unacceptable toxicity. The most frequent severe adverse events were skin-related, including another, less-aggressive form of skin cancer, and mild, reversible liver abnormalities. The most common reported side effects were rash, joint pain, hair loss and fatigue.

What I can’t find are published details, such as by how long life was prolonged in patients receiving the experimental drug. The NIH Clinical Trials site indicates the investigators aim to recruit 680 patients, and the Times indicates that since the trial opened, 338 patients were assigned to the chemotherapy arm of the trial, while another 338 received the Roche drug.

According to Amy Harmon’s report in the Times:

About half of the 68,000 Americans who develop melanoma every year have a mutation in a gene, called B-RAF, that goes awry, for reasons not well understood, signaling cells to grow uncontrollably. The Roche drug works by blocking a malfunctioning protein the gene produces in cancer cells, but leaving the functioning proteins in noncancerous cells alone.

Roche, in its press release, indicates that: “based on these interim analysis results, patients on the control arm of the study will have the option to crossover to receive RG7204.” The results will be presented formally at a medical meeting this year. (Presumably that would be the annual ASCO gathering in June.)

I’m eager to see the findings, the extent and duration of remissions, degrees of toxicity, and more. This could be another good example of targeted therapy – giving a treatment that’s designed to block a known molecular defect in a tumor – that might dramatically alter the prognosis, and way of life, for some patients with malignant melanoma. But I am cautious in my enthusiasm, as the reports so far, and data interpretation, come from the company that sponsored the clinical trial and would sell the drug if approved.

(all links accessed 1/20/11)

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addendum/clarification, Aug 2011: PLX-0432 was renamed vemurafenib.

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Steve Jobs Takes a Medical Leave

The big health story of the week, headlining the business news, is that Steve Jobs, Apple’s founder and usual CEO, is taking another medical leave. This is hardly a surprising development, given that the 55 year old corporate leader has had a complex medical course since at least 2003. In August, 2004 he told Apple employees he’d undergone surgery for an islet cell tumor of the pancreas. He received a liver transplant, said Methodist University Hospital in Memphis in the spring of 2009. According to multiple reports, lately he’s been looking tired and gaunt.

There’s a lot to learn from this case without delving into the private details. First, about cancer pathology – that not all cancers of the pancreas (or any organ) are the same. The NCI estimates that approximately 43,000 people (roughly half men, half women) are found to have pancreatic cancer, and over 36,000 adults will die of the disease each year in the U.S.

Steve Jobs holding an iPhone in 2010 (Wiki Commons)

But Jobs’ case is special: he had a neuroendocrine tumor, a kind of malignancy that can arise from hormone-secreting islet cells in the pancreas. In general, neuroendocrine tumors cause symptoms from the hormones they secrete or from local effects; a slow-growing tumor lump can press on nearby nerves, vessels or ducts. Neuroendocrine tumors, which can be distinguished from other glandular tissues by special stains and molecular tests, usually confer a relatively good prognosis. According to the NCI, islet cell tumors of the pancreas are quite rare, with estimates of between 200 and 1000 new cases per year.

A liver transplant is definitely a complicated matter, with its own sets of long-term issues, needed medications to reduce the likelihood of graft rejection, and potential complications. By all reports Jobs is not interested in going public with specifics now. Still, there’s abundant speculation about his condition; when you hold a high office in a publicly-traded company, your well-being matters.

At another level, some people may simply care how he’s doing. Jobs is a creative, public person who’s delivered Pixar movies and iPods and Macs, and who’s been ill in recent years. Taking a medical leave, when you care about your work and you love what you do, and you’ve invested much of your life in that, is no easy decision. I hope he gets well and feels better soon.

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Honoring MLK by Advocating Gun Control

I was trying to think of a medical story about Dr. Martin Luther King Jr. Today we officially celebrate his birthday: January 15, 1929.

Last year I considered the matter of donating blood, one of the many ways you might honor the leader’s commitment to a more civil and cooperative society.

MLK with RFK, both died of gunshot wounds (JFK Library, via Wikimedia Commons)

MLK and RFK, both killed by gunshot wounds (image from JFK Library, via Wiki Commons)

This year I’m struck by the fact that he died at the age of 39. On April 4, 1968, a rifle-wielding criminal in Memphis inflicted a lethal gunshot wound to King’s head and neck.

The recent Arizona shootings serve as a grim reminder of those tumultuous, bloody events. According to MSNBC, King’s son, Martin Luther King III, said: “When incidents occur like what we saw in Arizona, it shows us how much work we must do to create the kind of nation where nonviolence is embraced.”

Meanwhile, Congresswoman Gabrielle Giffords is healing in a Tucson ICU, after extensive neurosurgery and other life-sustaining procedures. This morning her husband, astronaut Mark Kelly, said on Twitter:

@ShuttleCDRKelly Mark Kelly
As my wonderful wife @Rep_Giffords continues to make progress, let us all pause and reflect on this MLK day.
11 hours ago

In honor of the day, and for the future, I wish that more physicians would speak out in favor of stricter gun control laws. Firearms present a public health issue in the U.S. According to the CDC, over 12,000 Americans die each year from homicide involving firearms. The number of non-fatal gunshot wounds requiring hospital care approximates 48,000 per year.

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Lessons from the Wakefield Case

I was almost at a loss for words today, besides having read the morning paper on the upcoming ESP study in a major psychology journal with questionable stats, and my having seen last night the first story on the British Medical Journal‘s report that completely, and maybe finally, discredits Dr. Andrew Wakefield’s anti-vaccine crusade which has caused needless morbidity and deaths in children from preventable illnesses in the U.S. and elsewhere.

So many others have written on Wakefield’s fraud, and considered the role of the press in perpetuating the notion that vaccines cause autism, I wasn’t going to cover it here on ML. But I do think there are a few instructive points from this “lesson” about medical communication and news:

1. People aren’t always rational in their decisions about health care. (This is an understatement.)

2. When most of the population (including journalists and, sadly, some doctors) are ignorant in basic science and statistics, misinformation spreads easily. In effect, our limited educations render us vulnerable to speculation and hype. A result “sounds good” or plausible, so we believe it, never mind the details –

3. Sometimes even educated people are so desperate for an explanation, or for a solution to a medical problem, that they’ll believe a smooth-talking scientist or doctor because they want to believe what he’s saying is true. If vaccines were to cause autism, that would give people a sense of control, i.e. a way to avoid autism.

The truth is that, for the most part, we still don’t know why diseases occur in some people and not in others. Not understanding can be a frustrating, unsatisfying circumstance, because it makes us feel powerless.

That’s it for today.

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A Reversal on End-of-Life Planning

The Obama administration will cut a new Medicare provision to compensate providers for discussing end-of-life care, according to the New York Times. This is an unfortunate reversal.

Too-often, doctors fail to have these discussions with their patients. This happens for many reasons including some physicians’ discomfort with the topic, their not wanting to diminish patients’ confidence in their healing powers, conflicts of interest (infusing chemotherapy is profitable; prescribing palliative home care is barely so, if at all) or simply being too busy to get around to the subject before a patient becomes critically ill and approaches death in an ICU setting. Most physicians need incentives to discuss palliative care options and end-of-life planning with patients in a thoughtful, not-rushed way.

The Medicare provision, which would have provided a small amount of compensation for doctors to spend time communicating with their patients about their preferences – whether they’d want to be kept alive on a ventilator with metastatic, refractory cancer, for example, or whether they’d want to be kept alive in a comatose state with a feeding tube for weeks or months or even years after suffering brain damage from low oxygen, might have helped some people get the kind of end-of-life care they’d choose, instead of what their doctors might give unthinkingly.

Again, I recommend that patients should be pro-active about their wishes. If your doctor doesn’t mention the topic, tell her what you want and document your wishes. Here’s a partial list of sites that provide related information on this subject:

Med­line­Plus on Advanced Direc­tives;

New York State: infor­ma­tion on Health Care Proxy forms and DNR orders

Medicare on Preparing for Your Future Health Care Needs

Fam­ily Care­giver Alliance on End-of-Life Choices

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After Breast Cancer, Get a Gym Membership!

Earlier this month the Journal of the American Medical Association (JAMA) published a myth-busting paper on weight lifting for women at risk for lymphedema after breast cancer treatment.  The study was neither large (154 patients at max, whittled down to 134 at analysis) nor high-tech (interventions involved gym memberships, weight training and lifting in neighborhood facilities like YMCAs).

The results were clear: working out with hand-held weights, carefully, is good for most women who’ve had surgery for breast cancer (BC).

Lymphedema, or swelling due to a damaged gland, can develop in a patient’s arm after removal of lymph nodes in the armpit. The uncomfortable condition can be disabling by impairing arm or hand movements. It affects a significant number of BC patients: among women who’ve had have just a sentinel lymph node removed, lymphedema affects roughly 6%; for those who’ve had complete axillary (armpit) lymph node dissection, the incidence is around 30%. There are roughly 2.5 million women living in the U.S. after a breast cancer diagnosis; most are at elevated risk for lymphedema.

Years ago, doctors commonly advised patients not to lift weights or perform strenuous exercises with their arms after a mastectomy or lumpectomy with lymph node dissection. To a lesser extent, this happens still today. As reported in the JAMA article:

Breast cancer survivors at risk for lymphedema alter activity, limit activity, or both from fear and uncertainty about their personal risk level, and upon guidance advising them to avoid lifting children, heavy bags, or other objects with the at-risk arm.9,10 Such guidance that deconditions the arm, increasing the potential for injury, overuse, and, ironically, lymphedema onset.11 Adherence to these precautions may limit physical recovery after breast cancer and, for some women, result in lost employment. Furthermore, activity avoidance may deter survivors from performing regular exercise…

The researchers recruited women in the Philadelphia area who’d undergone surgery for localized, unilateral breast cancer sometime between 1 and 5 years before the study. Each had at least 2 lymph nodes removed in surgery. The median age was around 55 years. The women were divided into two balanced groups before randomization – they received a year’s membership at a gym and a trainer for the first 13 weeks, or not.

So it’s good news that the women in “weight lifting intervention” group developed less lymphedema. What’s more, those women became stronger and sported a lower percentage of body fat. All of these differences were statistically meaningful and, for the most part, quite strong. Perhaps more remarkably, in a pre-planned subset analysis of women who’d had 5 or more lymph nodes removed, the proportion who experienced lymphedema in the weight-lifting group was only 7%, compared with 22% in the controls. That difference was highly significant, with a p-value of 0.003. The findings, in sum, show that it’s safe for women who’ve had breast cancer surgery to work out in a way that includes a careful, progressive upper body strengthening.

About a week ago, I was alerted to this article by Dr. Ramona Bates, a plastic surgeon who authors Suture for a Living. She’s had several recent, excellent pieces on this subject including a post on lymphedema and the JAMA report. I chose to write on this, in part, because it meshes with my professional and medical history.

In my case, I got conflicting advice on the matter. I wanted to continue swimming because it helps my scoliotic back. But some colleagues suggested that arm-intense strokes might be best avoided after mastectomies. A cosmetic surgeon rightly told me that some strokes might have untoward effects on implants. So I relied on my judgment: I chose to swim because it made me feel better and stronger. In the past year, I’ve started lifting a few small weights, carefully and slowly.

In the end, this is a story of a small clinical trial and the value of common sense in medicine. Weight lifting is not only safe; it can reduce the incidence of lymphedema in women at risk. But “old wives’ tales” still persist in some doctors’ minds; these need be dispelled. Finally, I can’t help but wonder what would happen if every woman could have a year’s membership at a local gym –

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Science Takes a Double Hit in the Press, Maybe

In his latest New Yorker piece The Truth Wears Off, Jonah Lehrer directs our attention to the lack of reproducibility of results in scientific research. The problem is pervasive, he says:

…now all sorts of well-established, multiply confirmed finding have started to look increasingly uncertain. It’s as if our facts were losing their truth: claims that have been enshrined in textbooks are suddenly unprovable. This phenomenon  doesn’t yet have an official name, but it’s occurring across a wide range of fields, from psychology to ecology. In the field of medicine, the phenomenon seems extremely widespread…

The Decline Effect, as Lehrer calls it, refers to scientists’ inability to reproduce reported results. The problem isn’t simple: it’s not just that different investigators or teams come up with conflicting information, or interpret the same raw data in disparate ways; over time, a single scientist may not be able to reproduce his or her own observations.

Lehrer begin his story with a target loaded with potential bias and conflicts of interest – a 2007 meeting in Brussels of scientists, shrinks and pharma executives contemplating the disappointing results in recent large clinical trials of blockbuster antipsychotic drugs like Abilify, Seroquel and Zyprexa. Initial reports, mainly from the early 1990s, which supported these drugs’ FDA approval and widespread use, turned out to present a too-positive story. Later studies indicate these agents are not as terrific as was advertised; new data call into question the drugs’ effectiveness and safety.

This is probably true, but it’s hardly surprising. It happens in oncology all the time – when drug companies support initial studies of new drugs with an intention to sell those, it’s sometimes the case (and unfortunately frequent) that initial reports are more promising than what really happens after a decades’ worth of less careful (i.e. more open) selection of patients who take an FDA-approved medication. Once you include a broader group of patients in the analysis, whose doctors aren’t researchers whose salaries are supported by the drug makers, the likelihood of getting truthful reports of side effects and effectiveness shoots up.

So I don’t think Lehrer’s big-pharma example is a reasonable shot at the scientific method, per se. Rather, it’s a valid perspective on problems that arise when drug companies sponsor what’s supposed to be objective, scientific research.

Lehrer moves on to what might be purer example of the decline effect. He tells the story of Professor Jonathan Schooler, a now-tenured professor who discovered in the 1980s that humans’ memories are strengthened by the act of describing them. The work is cited often, Lehrer says.

…But while Schooler was publishing these results in highly reputable journals, a secret worry gnawed at him: it was proving difficult to replicate his earlier findings. ‘I’d often still see an effect, but the effect just wouldn’t be as strong.’

Next, Lehrer steps back in history. He relates the story of Joseph Banks Rhine, a psychologist at Duke who in the early 1930s developed an interest in the possibility of extrasensory perception. (Yes, that would be ESP.) Rhine devised experiments to evaluate individuals’ capacity to guess which symbol-bearing cards might be drawn from a deck, before they’re drawn. The initial findings were uncanny: “Rhine documented these stunning results in his notebook and prepared several papers for publication. But then, just as he began to believe in the possibility of extrasensory perception, the student lost his spooky talent…”

Schooler, plagued with self-doubt about his published findings on human memory, as Lehrer tells it, embarked on an “ironic” attempt to replicate Rhine’s work on ESP. In 2004, he set up experiments in which he flashed images and asked a subject to identify those; next he randomly selected some of those images for a second showing, to see if those were more likely to have been identified in the first round.

“The craziness of the hypothesis was the point,” Lehrer says. “But he wasn’t testing extrasensory powers; he was testing the decline effect.” He continues:

‘At first, the data looked amazing, just as we’d expected,’ Schooler says. ‘I couldn’t believe the amount of precognition we were finding. But then, as we kept on running subjects, the effect size’ – a standard statistical measure – ‘kept on getting smaller and smaller.’ The scientists eventually tested more than two thousand undergraduates …’We found this strong paranormal effect, but it disappeared on us.’

OK, are we talking science, or X-Files? I find this particular episode – both in its original, depression-era version and in Schooler’s 1990s remake – fascinating, even thought-provoking. But these don’t change my confidence in the scientific method one iota.

He moves on to consider a zoologist in Uppsala, Sweden, who published on symmetry and barn swallows’ mating preferences, aesthetics and genetics whose Nature-published theories on “fluctuating asymmetry” haven’t stood the test of time. After an initial blitz of confirmatory reports and curious, related findings, the observed results diminished. Another scientist, said to have been very enthusiastic about the subject and who tried to reproduce them with studies of symmetry in male horned beetles, couldn’t find an effect. The researcher laments:

‘But the worst part was that when I submitted these null results I had difficulty getting them published. The journals only wanted confirming data. It was too exciting an idea to disprove…’

Next, Lehrer advances toward a more general discussion on bias in scientific publishing. This can only partly explain the decline effect, he says. Intellectual fads and journal editors’ preferences for new and positive results lead to imbalance in reporting. Publication bias distorts the reporting of positive clinical trials over negative or inconclusive results. No argument here –

Still, the problem goes deeper. Lehrer interviews Richard Palmer, a biologist in Alberta who’s used a statistical method called a funnel plot to evaluate trends in published research findings. What happens, Palmer says, is that researchers are disposed (or vulnerable?, ES) to selective reporting based on their unconscious perceptions of truth and uneven enthusiasm for particular concepts. He gives an example:

…While acupuncture is widely accepted as a medical treatment in various Asian countries, its use is much more contested in the west. These cultural differences have profoundly influenced the results of clinical trials. Between 1966 and 1995, there were forty-seven studies of acupuncture in China, Taiwan, and Japan, and ever single trial concluded that acupuncture was an effective treatment. During the same period, there were ninety-four clinical trials of acupuncture in the United States, Sweden, and the U.K., and only fifty-six percent of these studies found any therapeutic benefits.

These discrepant reports support that scientists see data in ways that confirm their preconceived ideas. “Our beliefs are a form of blindness,” Lehrer writes. In Wired he quotes Paul Simon: “A man sees what he wants to see and disregards the rest.” The point is clear.

Nearing the end, Lehrer draws on and extends upon David Freedman’s November Atlantic feature, Lies, Damned Lies, and Medical Science, on the critical, outstanding oeuvre of John Ioannidis, a Stanford epidemiologist who elucidates falsehoods in published research.

Re-reading these two articles together, as I did this morning, can be disheartening. “Trust no one,” I recalled. Seems like many – and possibly most – published research papers are untrue or at least exaggerated and/or misleading. But on further and closer review, maybe the evidence for pervasive untruths is not so solid.

In sum, the Truth Wears Off, in last week’s Annals of Science, offers valuable ideas – the decline effect (new), the statistician’s funnel plot (not new, but needing attention) and publication bias (tiresome, but definitely relevant). The ESP story is an obvious weak link in the author’s argument, as is the article’s emphasis and reliance, to some degree, on psychological models and findings in relatively soft fields of research. Physics, genetics, molecular biology and ultimately most aspects of cancer medicine, I know and hope – can be measured, tested and reported objectively.

My approach to new information is always to keep in mind who are my sources, whether those are authors of an article I’m reading or a doctor who’s making a recommendation about a procedure for someone in my family, and the limitations of my own experiences. I’m skeptical about new drugs and medical tools, but determinately open-minded.

The problem is this: if we close our minds to all new findings, we’ll never learn anything. Nor will we ever get better. Sometimes scientific reports are accurate, life-saving or even paradigm-shifting; if only we could know which those are –

“When the experiments are done, we still have to choose what to believe,” Lehrer concludes.

He’s right; I agree. Our choices, though, should be informed – through literacy, multiple sources of information, and common sense.

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The Loss of Elizabeth Edwards

Dear Readers,

I am sad to learn of the death of Elizabeth Edwards, who died earlier today of metastatic breast cancer at the age of 61. She has taught countless people about what it’s like to live with cancer.

My thoughts are with her family now.

-ES

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Notes On a New Kind of Anticoagulant

On the hematology front –

Last weekend at the annual meeting of the American Society of Hematology (ASH), researchers presented data on a new kind of blood thinner. Rivaroxaban (Xarelto) is a pill that works by blocking the activated form of human clotting factor X (Xa). The NEJM published the EINSTEIN* findings on-line ahead of print, coincident with the presentation.

The research includes two reported trials. In the first, an open-label randomized study of 3449 patients with acute deep venous thrombosis (DVT), subjects received either rivaroxaban pills or a standard treatment regimen starting with an injected blood thinner (enoxaparin) followed by an oral Vitamin K antagonist, like coumadin.  The main findings in this Acute DVT Study was that the new drug, rivaroxaban, is as good (“non-inferior”) in terms of preventing recurrent clot as is the older regimen and bears a similar safety profile.

The second, parallel EINSTEIN-extension trial involved randomization of 1197 patients after treatment for acute DVT to take oral rivaroxaban or a placebo for an additional 6-12 month period. In this study, patients taking the experimental anticoagulant had fewer blood clots than those on placebo. Unsurprisingly, there was a slightly increased reported incidence of major bleeding (4 patients, 0.7%) in patients on the blood thinner relative to placebo (0 patients, 0%). This difference was not statistically significant.

Both trials were funded by Bayer Schering Parma and Ortho-McNeil. According to a Bayer press release of last August: “If approved by the FDA, Ortho-McNeil, a division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. (a Johnson & Johnson Company), will commercialize rivaroxaban in the U.S.”

What’s good, clearly, is that several effective anticoagulants are emerging as alternatives to heparin, which must be injected, and coumadin. In October the FDA approved the first of these drugs, dabigatran (Pradaxa), for prevention of stroke in patients with atrial fibrillation. This was big news in cardiology circles, with reason. Another area of use for these agents would be in prophylaxis for DVT in patients who undergo hip replacement and some other kinds of major surgery.

In my experience as a hematologist, and as a patient who’s had a DVT, I know that coumadin dosing is not straightforward. Because the therapeutic dose varies so much among individuals in ways that depend on genetic factors and potentially change over time with diet, patients need provide initially frequent and then periodic blood samples. The repeated blood tests don’t require large amounts of blood, but they’re annoying and costly. What’s more, the hassle – pain of blood draws, driving or walking to a clinic for sample taking, waiting for results – interferes with quality of life.

Giving intravenous blood thinners is not convenient either, as these need carefully-monitored infusion of the drug, and it’s easy to overshoot or undershoot the dose. Injectable blood thinners like low molecular weight heparin are easier to dose than conventional heparin, but still it’s pretty unpleasant for a patient to have to inject herself once or twice a day with a needle.

Soon we’ll see what the FDA says about rivaroxaban. I’m not excited about this one agent as opposed to any other, but I am enthusiastic about this new class of drugs. These should benefit people whose medical conditions warrant the use of blood thinners.

*The “EINSTEIN” investigators are based in the Netherlands and are listed in the original paper. It’s hard to find an explanation of the acronym.

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The Transportation Safety Authority Screens Travelers Inside and Out

I’ll be staying near my home in Manhattan this week. But if I did have plans to travel by airplane for the holiday, I think I’d be apprehensive about the new screening procedures implemented by the Transportation Safety Authority (TSA).

My concern is not so much with the scanners. (For a detailed review of these machines, I recommend this article in Popular Mechanics.) There are two types of scanners in current use: millimeter wave machines, which use radio-frequency waves to generate 3-D images, and back-scatter units which, by design, use low doses of x-rays to visualize what’s inside a person being scanned.

Rather, I’m worried about screening errors – false positive and false negative results, and about harms – physical and/or emotional, that patients and people with disability may experience during the screening process.

In the context of travelers’ screening, a false positive occurs when an examiner thinks he or she sees or feels something abnormal – say a weird expression on a passenger’s face or when an initial, low-threshold alarm goes off somewhere in the system – but the person isn’t carrying any dangerous or contraband items. That early, false positive signal puts the traveler through extra procedures, possible embarrassment and/or stress.

A false negative happens when a screener misses an explosive device or other harmful material. A good example is the so-called Christmas bomber, who last year got through airport security and boarded a plane with explosives effectively hidden in his underwear. In that December 2009 instance, the examiners failed to identify a passenger who carried a potentially lethal weapon. The TSA’s goal should be to minimize the number of false negative screening tests. That’s because we wouldn’t want someone to get through screening and board a plane while carrying a weapon.

The problem is that it’s easy to imagine an imperfectly-trained, inexperienced or just plain tired screener missing an irregularity in someone’s 3-D or other kind of whole-body image, especially in the context of a steady stream of passengers rushing to catch flights. The operators might miss weapons despite the visual “information” available, right in front of their eyes.

So I don’t object to the new technology, which should increase the accuracy of the screeners’ function. Ultimately, though, we can’t get around the fact that TSA employees are human and some will be nearing the end of their shift; the scanners can reduce but not eliminate these kinds of errors.

My second concern is with the potential harm to patients and people with disabilities. People may be harmed physically if, for example, a screener mishandles a pump or other device. There’s been a lot of attention to one recent report, that of a 61 year old man with a history of bladder cancer whose urostomy bag ruptured during an airport pat-down. The man described his urine spilling, and his feeling humiliated.

This is a very understandable reaction; as someone who has implants after mastectomies, and who carries a lot of internal metal hardware in her spine and elsewhere, with scars galore, I know how damaging can be a stranger’s scrutiny. Unlike doctors and nurses, most TSA employees are not accustomed to seeing colostomy bags, stumps and other disfigurements usually hidden under a person’s clothing. Even an accidental, unkind expression in a look-over, or an insensitive pat-down, could make a person feel pretty bad about their ailment.

Of course we don’t have to travel on airplanes. I don’t see this as a civil rights issue; I don’t think there’s a right to board a public vehicle without full screening if the TSA deems it’s necessary for public safety. Rather, I accept that an aspect of having illnesses is that sometimes you have to put up with things other people don’t experience.

What would help, clearly, is better sensitivity and training of TSA staff, as was considered in response to the urostomy incident. But given the huge volume of travelers and enormousness of our complicated transportation system, it seems unlikely we’ll get a satisfactory solution among all staff at all airports, at least not in time for Thanksgiving.

From the patient’s perspective, there are some practical points that might help. Amy Tenderich, at Diabetes Mine, offers tips for individuals with insulin pumps. Trisha Torrey has an interesting piece on her Patient Empowerment blog (where she argues that this is not an empowerment issue) and recommends a simple, common-sense approach, which is to arrive early at the airport. As for me, I carry cards indicating the dates of my surgeries and the nature of my hardware. Now, I’ll add to those a note from my doctor.

Meanwhile I hope the screeners will use their new equipment to do a better job at detecting people carrying weapons. And that those individuals who plan to boycott the scanners with a National Opt-Out Day tomorrow, will change their minds. The TSA employees have enough on their hands already, without a demonstration; it’s in everyone’s interest that the screening be effective, hopefully 100 percent, in this holiday season.

minor rev: 11/23, 2PM

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Lots of Excitement about Anacetrapib, a Cholesterol-Lowering Drug

I’m a bit puzzled by all the excitement about Merck’s new drug, Anacetrapib (MK-0859), that’s said to lower risk for cardiovascular disease by lowering bad cholesterol. Earlier this week at the annual meeting of the American Heart Association, researchers presented promising findings on the drug, including results from the phase III DEFINE (Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib) trial. The list of disclosures for that abstract is long and fairly shocking. On Wednesday, the results were published on-line in the NEJM.*

The new drug interests me, as an oncologist, because it’s an enzyme inhibitor – in some ways like many new and in-the-pipeline cancer treatments. Anacetrapib raises high-density lipoprotein (HDL, a.k.a. “good cholesterol”) and lowers low-density lipoprotein (LDL, a.k.a. “bad cholesterol”) by interfering with a cholesterol enzyme transfer protein (CETP). The experimental medication is a pill that, based on earlier safety studies, is taken at 100 mg by mouth, once daily. So it’s convenient enough.

In some respects, the results of this randomized, placebo-controlled large trial are knock-your-socks-off impressive: patients on the drug had, an average, a more-than doubling of their serum HDL levels, from 41 to 101 mg per deciliter.** At the same time, the HDL shift was just 40 to 46 for patients assigned to the placebo (control). Conversely, LDL levels went down dramatically in patients taking Anacetrapib, from 81 to 45 mg per deciliter on average, and the corresponding drop seen among the control patients was only 82 to 77. These numbers are really terrific, and the results highly significant from a statistical perspective. The study lasted for 76 weeks, i.e. well over a year, and the drug was very-well tolerated according to all published reports.

What’s wrong here? Well, it’s that we don’t know for sure how this new drug affects heart disease and other vascular conditions. In this study, the plasma cholesterol levels were monitored as surrogate markers for risk of atherosclerotic events, but these laboratory parameters are not the same thing as direct measures of disease. It is uncertain if this drug has any impact on mortality, or even on heart attacks, strokes or other clinical endpoints.

In my opinion, we need a lot more information about this new drug before we prescribe it to thousands or millions of people who have hyperlipidemia. Fortunately, as pointed out by Dr. Harlan Krumholz, writing for Forbes, Merck is “doing the right thing” by testing the drug in additional studies now, with clinical endpoints in mind. Still, his enthusiasm for what amount to very favorable blood testing seems extreme in light of the previous experience to which he refers with Pfizer’s torcetrapib, a drug of the same class that turned out to have significant side effects, and Merck’s previous marketing of Zetia.

According to the New York Times, John Boris, an analyst at Citigroup, wrote in a note to investors on Wednesday that the drug could potentially have sales of more than $1 billion a year. Dr. Steven Nissen, a sometimes cautious leader in the field, found the results encouraging, according to widely-cited comments such as those appearing in the Dow Jones Newswires.

In a few years, we’ll see what Merck finds out with the ongoing trials, and if the drug really helps reduce heart attacks and deaths in people with hyperlipidemia.

Meanwhile, since my cholesterol’s crept up, just a bit above 200, I’ve started eating oatmeal and quinoa more often. I take only skim milk in my cereal at breakfast, cut out most cheese and pizza, and enjoy ice cream but occasionally. I don’t wish to ingest any experimental enzyme inhibitors that aren’t essential in the life-saving sense.

The NIH offers tips for therapeutic lifestyle changes that can help reduce hyperlipidemia in many patients.

*subscription may be required

**cholesterol units: milligrams per deciliter

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Noting the Death of Jill Clayburgh Who Lived For 21 Years With a Chronic Form of Leukemia

I was saddened yesterday to learn of the death of Jill Clayburgh. The 66 year old actress died on Friday in her Connecticut home. According to ABC news and the LA Times among other reports, she’d had chronic lymphocytic leukemia (CLL) for 21 years. This means she lived with CLL for nearly a third of her life.

It happens that I used to spend much of my time thinking about CLL; it was the focus of my laboratory’s research program, and I cared for many patients with this particular form of leukemia.

It’s an instructive disease at several levels:

Chronic lymphocytic leukemia is the most common form of leukemia in adults in Europe and North America. The National Cancer Institute reports that there are approximately 15,000 new cases each year in the U.S. Although CLL is not curable, it is an indolent type of tumor, a slow-growing cancer a person might live with for years and even decades. For this reason, it is perhaps the best example of a malignancy for which a “watch and wait” approach is often, but not always, appropriate.

By now, in 2010, it seems the public has a good sense that the big C, i.e. “cancer” is not one disease, but many. For leukemia it’s the same deal: there are at least several dozen forms, perhaps over a hundred identified by now. The nomenclature can be confusing to people who receive a new diagnosis and to doctors, as well, who many not be up-to-date on new molecular classification schemes.

The image to the left, from Wikimedia Commons, reveals a high-power magnification (1000 X) of a Wright’s stained peripheral blood smear from a patient with CLL. The lymphocytes, with the darkly staining nuclei and scant cytoplasm, are CLL cells.

A helpful framework, I find, for understanding leukemia is to think, first, in terms of what kind of cell has become malignant in each case – what an oncologist would call the cell of origin for the tumor. Leukemia is, by definition (from the Greek roots leuk, for white, and haima, of blood) an excess of white cells in the blood. But there are multiple kinds of white blood cells, and each type can form one or more type of leukemia. The most basic leukemia categories are three: tumors of myeloid cells, such as neutrophils and their precursors; tumors of lymphocytes, such as T or B cells; and tumors of other white blood cells that are less common in the circulation. CLL is a tumor of B-lymphocytes, the kind of white blood cells that normally mature to form antibodies.

A second way of classifying leukemia is based on the rapidity of tumor cell growth. In CLL, the malignant B cells tend to divide slowly, rendering this a chronic, i.e. indolent disease in most cases. Now, the disease might be detected in its earliest phases upon routine blood testing, sometimes years before it would become clinically apparent by causing symptoms like uncomfortably swollen glands or fatigue from anemia.

Here are some websites that provide open-access information about CLL:

American Cancer Society

Cancer.net (ASCO)

Leukemia & Lymphoma Society

MedlinePlus

National Cancer Institute

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What Not to Wear In the Hospital While Recovering From a Stroke

Today’s Annals of Internal Medicine includes new results for the CLOTS (Clots in Legs Or sTockings after Stroke) Trial. Not-quite acronyms aside, it’s an interesting study with implications for many patients at risk for deep venous thrombosis (DVT).

compression stockings - NIH image (Medline Plus)

This U.K.-based study, involving 3114 patients in 112 hospitals in 9 countries, used ultrasound to evaluate possible DVTs in legs of people after they’d been immobilized upon suffering strokes. Patients were randomized to receive either thigh-length or below-the-knee compression stockings while recovering in the hospital. The main result was that 98 of 1552 (6.3 %) of patients who received thigh-length stocking and 138 of 1562 (8.8%) of patients with below-the-knee stockings developed DVT. This difference is highly significant (p = 0.008).

The twist is this: in a separate, extensive recent Cochrane review the investigators compiled data from multiple randomized studies of stockings in stroke patients and established that thigh-length stockings were inferior to no stockings, i.e. stroke patients who wore thigh-high compression stockings were more likely to develop DVTs than those who didn’t wear any stockings at all. The authors reconcile these separate results by suggesting that below-knee stockings might increase the risk for DVT after stroke.

Confusing? Yes. The bottom line is that thigh-high compression stockings may not help, based on the Cochrane analysis; below-the knee stockings may hurt.

Why this matters is that the results have implications for other hospitalized patients at risk for DVT, like people who’ve had hip replacements, pelvic or spine surgery. “Unfortunately, no randomized trials have compared below-knee stockings with no stockings,” the authors write.

An accompanying editorial in the Annals considers the “puzzling” findings of the CLOTS trials and addresses how clinicians might prevent DVT in patients with stroke:

…The unexpected findings that thigh-length stockings are not very effective at preventing venous thromboembolism and that below-knee stockings might increase incidence of thrombosis in patients with stroke should prompt a reevaluation of the role of graduated compression stockings in other groups of patients….Clinicians need to realize that despite the ubiquity of graduated compression stockings in many settings, the net benefits and risks of this seemingly innocuous intervention remain uncertain.

As a hematologist, I see this as a low-tech, big deal because DVTs are a huge source of morbidity and mortality.

In the U.S., the number of clots per year runs in the hundreds of thousands. DVTs tend to arise in people who are immobilized after surgery, with neurological impairment and during travel. The elderly are particularly susceptible, as are pregnant women and people with inherited clotting dispositions. The National Blood Clot Alliance provides an interactive map of the incidence of DVTs, state by state, on its website.

Personally, I love it when the doctors allow me to take off the boots when I wake up after a procedure, so I can kick my feet around and, I hope, reduce my risk of DVT by movement and exercise. Compression stockings feel like corsets on my calves; they’re warm and constraining. On planes, too; I find stockings restrictive.

My own experience aside – the data supporting the use of compression stockings are limited, and this new study suggests they can be damaging.

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Notes on Cholera, Old and New

Cholera was a far-away kind of affliction, almost an abstraction, when I first studied microbiology in 1984. The legendary, infectious scourge still affected people in places like Bangladesh or Indonesia, but was a treatable condition that, surely, would be eradicated within a decade or so through progress, if you could call it that, like basic plumbing and sanitation.

The tiny comma-shaped bacteria, Vibrio cholerae, tend to thrive in brackish water, the kind that’s just a bit salty from a mix of ocean and fresh sources. These sometimes stagnant watery places crop up in river deltas, like the Ganges, and coastal estuaries such as those along the U.S. Gulf Coast. We learned that you might, very rarely, pick up a case of cholera by eating contaminated shellfish like crabs or oysters.

The most common symptom of cholera is diarrhea, so rapid and voluminous that a person can die, quickly if without remedy, by straightforward dehydration. The diagnosis of cholera can be tricky, as many people are afflicted with severe gastrointestinal diseases worldwide, but most don’t have this particular, potent toxic germ. Cholera spreads by contamination of infected human feces in the water supply. The disease can afflict people who drink tainted water, who touch it and then put unclean fingers into their mouths, as children do, and who eat food prepared by those with affected hands.

illustration by Robert Seymour (1831), image from the National Library of Medicine, image A021786

Choleraphoby, illustration by Robert Seymour (1831), lithograph from the National Library of Medicine, Image #A021786

Dr. John Snow, an anesthesiologist and founder of public health, recognized the means of cholera’s spread more than 150 years ago in London, where he became famous for mandating the closure of the Broad Street Pump. Snow died at the age of 45, of what was said to be apoplexy, old jargon for a stroke.

In 2009, there were 221,226 cholera cases reported and 4,946 cholera deaths in 45 countries, according to the CDC. Based on information put together by the World Health Organization, the case-fatality rate is 2.24%. A trend in recent years is that the overwhelming majority of cases, roughly 99 percent, are reported in Africa.

According to the 17th edition of Harrison’s Principles of Internal Medicine, there have been seven global cholera pandemics since 1817. The current rage, attributed primarily to the El Tor biotype, started in Indonesia around 1961. That strain spread, eventually, as far as coastal Peru in the early 1990s. There have been no cholera epidemics in North America since the middle of the 19th Century.

What’s happening in Haiti now is the real deal, says the CDC. Thousands are infected, mainly in towns along the Artibonite River, which squiggles on the map and in real terrain through the western section of Hispaniola, north of Haiti’s capital, Port-Au-Prince. Among other concerns are the vast numbers of people living without toilets in tent cities and slums outside of the capital, especially since an earthquake devastated the region last January.

The CDC offers some very practical tips for people who live or travel in areas where cholera is endemic. Most people who are exposed to cholera and survive become immune, although infectious strains vary and immunity may not be long-lasting. In the U.S. there is no available vaccine for cholera, according to the CDC. Treatment consists primarily of giving electrolyte solutions, for rehydration, and antibiotics in some cases.

Now, the mortality rate from cholera in Haiti is running just under 10 percent, according to today’s news. Hopefully, doctors from MSF and other agencies working in the region will get this epidemic under control. But already it’s clear that hundreds of lives have been lost to an illness that it seems should have been eradicated long ago.

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Copiapó Dreaming – The Copper Miners’ Tale

This week it seemed at least half the world was captivated by the uplifting story of the Chilean miners. The 33 men – mainly middle-aged and of modest means – zoomed up in high-tech capsules from the deep, would-be tomb where they’d been waiting for 69 days underground in the southern Atacama, not far from the industrial, northern Chilean city of Copiapó.

The amazing and nearly-too-good-to-be true news is that a top-notch team of engineers, doctors including the NASA/Johnson Space Center Deputy Chief Medical Officer, nurses, psychologists and others pulled off this fantastic rescue by which each and every one of these real men were delivered to Camp Hope (Esperanza) a tent city swelling with media and enthusiastic politicians, clergy, miners’ families and, presumably, support staff – cooks, washers and others who helped people there cope with the situation.

It’s inconceivable that any human with a heart would not be gladdened upon learning of the miners’ safe arrival – all more-or-less in good shape, no less – on firm ground. A rabbi said this of the affair: we too-often take this world for granted; but after their ordeal in the darkness, the Chilean men kissed the earth and thanked god for simply returning them to what they’d had before – a place filled with sunlight, air, loved ones, friends, food, music and, well, everything they had and have again. So there’s a religious message here, if you’re open to that. At the same time, an atheist would see clear evidence in this fantastic episode for the power of humans and science, technology and coordinating resources.

The medical issues are rich, including: risk of fatigue and dehydration in an inescapable, 90 degree hot and humid environment; vitamin deficiency and possible eye damage upon exiting, from lack of sunlight; lung problems from metal dust exposure; infections like pneumonia, potentially shared in a small communal space or gut-related, if hygiene is poor and human waste is not stashed properly; emotional downers – like fear and depression – may affect men who don’t articulate those sorts of concerns.

Some environmentally-minded thinkers point out that this true tale isn’t representative, reducing the story like this: “For every miner who was rescued before the cameras this week, more than 400 others will die this year.” Indeed, the International Federation of Chemical, Energy, Mine and General Workers’ Unions, estimates that worldwide, approximately 12,000 miners will lose their lives this year, while on the job. They’re right, I know – mining is a risky, under-regulated occupation.

Nonetheless, I’m thrilled by this remarkable story, at two levels: first, that the “patients” are all right, and second – what’s even more awesome – is that people around the world cared so much about the miners’ well-being. I’ve been wondering what if the outcome hadn’t been so successful. The news coverage would have been less intense, and the President of Chile would have had more difficulty maintaining his political position, and maybe there’d be more regulation of copper-mining in the future. Still, it would have been OK, good and maybe great, I think – even without the happy ending – that the engineers and international top-docs with their expertise, and miners’ families and lovers’ with their food and good cheer, did everything they could.

The outcome matters, but so does the effort, in itself. If we don’t as much as offer care to humans who need it, there’s little chance they’ll get better. This news is about health care, delivered. So the next, logical question is this: Can we take this up to another level by providing high-quality, coordinated care to every group of 33 patients with a guarded prognosis, and do whatever it takes to make them well using existent technology and medicines? This story is a fantasy, as much as it’s real.

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Everybody’s Talking About Stem Cells

Last week, doctors injected embryonic stem cells into a human patient with an acute spinal cord injury. The procedure took place at Shepherd Center, a hospital and research center for spinal cord and brain injury in Atlanta, GA. The patient was the first to receive human stem cells derived from an embryo in an FDA-approved research protocol in the U.S.

The phase I trial, sponsored by Geron Corporation of Menlo Park, CA, is primarily intended to evaluate the treatment’s safety. The company has developed a way to culture and purify oligodendrocyte progenitor cells (OPCs – primitive neuronal cells) from human embryonic stem cells (h-ESCs). These precursor cells, obtained from human embryonic tissue, can be coaxed, at least in vitro, to develop into one of various mature cell types, including neurons).

So what defines stem cells?

Stem cells are considered pluripotent, meaning that they have the capacity to differentiate, or mature, into specialized, distinct cell forms depending on nearby cells and stimulatory molecules in their environment. Mature cells, by contrast, have already “decided” what kind of tissue they’ll grow into – whether that’s part of the eye, or the heart, liver tissue, nervous system or any other body component.

The idea behind stem cell therapy for spinal cord injury is to provide the wounded spine with fresh, primitive cells that might grow into neurons and replace those that have been damaged. The protocol is highly-experimental.

There are three major sources of human stem cells:

1. Adult stem cells are relatively abundant in the bone marrow.

2. Cord blood cells; as are found in the placenta and umbilical cord after delivery of a newborn;

3. Embryonic stem cells, as were used in this protocol, are typically removed from surplus material after IVF.

You can learn more about human stem cells on the NIH website here.

(and belated happy birthday, JL!)

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A Lead Poisoning Outbreak in Nigeria, Plumbism and Anemia

Over 400 Nigerian children have died from lead poisoning this year, the Times reported yesterday. The outbreak is centered in five villages in the northwestern state of Zamfara.

Small-scale gold mining in the region leads to lead toxicity, as follows: “In an attempt to extract gold from ore rich with lead, miners crush and dry the ore, often inside their own homes. The soil and in some cases the groundwater get contaminated,” according to an Oct 5 field report from Doctors Without Borders/Médecins Sans Frontières (MSF).

I learned long ago that lead poisoning is sometimes called plumbism, stemming from plumbum, the Latin term for lead (Pb, atomic number 82), a metal used by plumbers. A rarer term is Saturnism, based on the metal’s association with the planet and ancient Roman god.

Now, in the U.S., lead poisoning most commonly comes from environmental toxins like lead-based paint. It affects children, who may eat flakes of peeling, lead-based paint or accidentally ingest lead by licking or eating toys or jewelry that contain this toxic metal. The problem occurs in adults, too, typically from unknown sources.

The EPA provides some helpful information on its website. Lead poisoning can be subtle; common symptoms are fatigue and poor concentration. Doctors may detect anemia, and upon inspection of a patient’s red blood cells might find characteristic basophilic stippling. The National Institute of Environmental Health Sciences (NIEHS) reports that lead toxicity declined dramatically from 1980 to 2000 in the U.S.

lead poisoning; arrows point to characteristic basophilic stippling (attr: Herbert L. Fred, MD and Hendrik A. van Dijk, Wikimedia Commons)

In northwest Nigeria, MSF workers are treating some of the affected children and nursing mothers with chelating agents; these metal-binding compounds clear lead from the bloodstream and, to some extent, remove it from body organs where it’s already deposited. The World Health Organization (WHO) issued a bulletin on lead poisoning from gold-mining in Nigeria in June, 2010.

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Notes on the 2010 Swedish Mammography Report, and the Press

I’m not sure why editors buried last week’s report on the new Swedish mammography study. The positive findings appeared only on page 24 of Thursday’s (Sept. 30) print edition of the New York Times. My husband didn’t hear about it on NPR on his way home from work. The moms in my community didn’t see Dr. Gupta talking about this on TV.

The new findings – linking mammograms for women aged 40 to 49 to a big drop in BC death rates years later – seem to confound journalists’ notions on screening’s lack of effectiveness in this disease. But they’re no surprise to doctors like oncologists who have experience caring for breast cancer patients.

The Swedish study, with lead and senior authors in the Department of Radiation Sciences at an oncology center at Umeå University in Sweden, was presented at an annual ASCO* breast cancer symposium and published on-line** last week in the ACS journal Cancer. The data reveal that for women living in Sweden where mammography was offered every 18 or 24 months to women ages 40 to 49, breast cancer-related deaths fell by approximately 26 percent.

In some ways, the new report is similar to a highly-publicized paper published a week earlier in the NEJM: both are based on historical data, between 1986 until 2005, extracted from comprehensive, public databases in a Scandinavian nation. What’s different here, besides the positive results and younger age group focus, is that follow-up was much longer in this Swedish study: 16 years after a BC diagnosis; it was a measly 2.2 years in the Norway study.

Adapted from Fig 2 in Swedish study; the blue arrow points to ~2.2 yrs, the average follow-up in the Norwegian data

This graph to the right, adapted from Figure 2 in the original Swedish report, shows the crude cumulative breast cancer mortality per 100,000 person-years. The solid line shows survival for women found to have BC in the study group – those women living in areas where mammography was provided between ages 40 and 49; the dashed line shows the same for the controls – those living in areas where women between 40 and 49 years “were not invited to attend” service (i.e. government-financed) screening.

The light blue arrow, which I’ve added, points toward the 2.2 year mark, the average follow-up for patients in the recent Norway study. What’s evident is that such a short interval is not nearly sufficient – it’s far too early – to assess the effects of mammography on mortality in women with BC; over years, the divergent curves show a marked benefit of screening.

As an oncologist, I know this finding meshes with reality; breast cancer tends to kill women years, rather than months, after the time of initial diagnosis; you wouldn’t expect mammography to make a dent in a mortality curve until after 4-5 years or so, especially if you factor in possible lead-time bias, as the Swedish study authors did.

Some legitimate concerns about the Swedish study include that it comes from a radiology group with an “interest” in having mammography be effective. Let’s say that’s true, but it also may be that those physicians become breast cancer researchers with good intentions, and that mammography does save lives by catching early-stage BC. It would be foolish to deny that radiologists, oncologists and others in the field have the most experience with breast cancer imaging, diagnosis and treatment.

This positive report should be scrutinized, yes, but no more or less than the other papers on the same subject that have been highlighted, selectively, in the media. How journalists cover mammography studies, and that they do so with an open mind, matters a lot.

*disclosure: I am an ASCO member.

**full-text by subscription

***Hellquist, B. N., Duffy, S. W., Abdsaleh, S., Björneld, L., Bordás, P., Tabár, L., Viták, B., Zackrisson, S., Nyström, L. and Jonsson, H., “Effectiveness of population-based service screening with mammography for women ages 40 to 49 years,” Cancer, 2010, Volume and pages pending (on-line only, citation in progress)

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What’s Missing in the Recent Mammography Value Study

This week’s New England Journal of Medicine includes an article*on the potential benefit of breast cancer (BC) screening by mammography. The paper, authored by a group of epidemiologists and biostatisticians from the Cancer Registry of Norway, Harvard University, the Dana Farber Cancer Institute and Stockholm’s Karolinska Institutet, suggests that mammography has a relatively small influence on survival.

The work, along with an accompanying editorial* by H. Gilbert Welch, M.D., M.P.H., got front-page attention in the Times and elsewhere. My friends want to know why this particular research study was featured and, really, what it showed.

So here’s my take –

The analysis:

The researchers studied chronological trends in BC diagnosis and mortality in Norway. To see if mammography had an effect, they divided the country into two groups, “screening” and “non-screening,” based on when a state-sponsored mammography screening program was implemented in each of 19 counties there. The national plan, which required that each region establish a centralized, multidisciplinary BC care team before participation, began in 4 counties in 1996 and gradually expanded to include all of Norway by 2005. According to the authors, all Norwegian women between the ages of 50 and 69 years have been asked to participate in screening mammography since 2005; 77% have done so; Norway’s nationwide cancer registry is nearly 100% complete.

They evaluated a total of 40,075 women (“subjects”) who received a diagnosis of BC between 1986 and 2005.

Major findings:

For women between the ages of 50 and 69, BC-associated mortality** fell from 25.3 to 18.1 in counties where a government-sponsored mammography program was implemented early on, and from 26.0 to 21.2 in counties where mammography was not covered, over a similar time frame. Because BC-associated mortality declined in all regions of Norway, regardless of whether mammography was offered, the authors conclude that screening can’t account for all the reduction in mortality.

By their calculations, mammography accounts for roughly 10 percent of the enhanced survival. (This finding was not statistically significant.)

The authors suggest that recent progress in BC survival – which in their study improved significantly in all regions of Norway – comes, for the most part, from better care and treatments.

What’s wrong with the paper? I see several key flaws:

1.  The average follow-up is only 2.2 years after diagnosis, with a maximum follow-up of 8.9 years (“Results,” p. 1206). This is far too short a follow-up interval to measure the benefit of mammography or any sort of intervention in women with breast cancer. When BC recurs it’s often after several years and, occasionally, decades later.

2. Among women under the age of 50 there was a slight increase in BC-mortality noted: A non-significant relative increase in mortality, of 4%, after the introduction of the screening program for older women (p. 1207, Table 1). This worrisome finding is not adequately addressed by the authors; one might wonder – did fewer women in their forties go for mammograms after 1996, since they were only recommended and covered for older women? (My concern is that reduced screening, now, in younger women might lead to an increase in BC mortality.)

3. Digital mammography was not evaluated in this study.

4. The authors detected the greatest benefit of screening among women with Stage II BC; there was a “marked” 29% reduction in mortality relative to the historical counterparts for that group who were screened, as compared to only a 7% reduction in mortality for women with Stage II tumors in counties where screening was not available over the same historical interval (p. 1207). This observation suggests that mammography screening is most life-saving for women with Stage II tumors. As an oncologist, I find this highly-plausible; the purpose of mammography is to identify tumors in early stage and spare women morbidity and mortality associated from advanced disease.

5. There’s no mention of the absolute number of lives saved by the procedure according to the authors’ calculations, but I think this is an important number to keep in mind when we assess the procedure’s value. If the paper’s conclusion is true – that mammography reduces BC-associated deaths by just 10 percent – then in Norway, with a total population of 4.8 million and where some 4,791 women in the study died (p. 1206), these results support that mammography spared approximately 480 lives in those 20 years.

My spin:

Mortality in the U.S. from breast cancer has declined by roughly a third since the implementation of wide-spread mammography screening. Here, where some 45,000 women die each year of BC, we’d save 4500 lives per year if the added value of mammography is just 10 percent, as suggested by the new study. If the benefit of screening mammography is higher – in the range of 45 percent, as was supported by a 2007 paper, also published in the NEJM – then the value would exceed 20,000 women’s lives per year. If the benefit is only 25 percent in terms of reduced mortality, that would result in over 11,000 lives saved, per year in the U.S.

As for the editorial, first I’ll say that the opening statement – that “no screening test has ever been more carefully studied than screening mammography,” is misleading. While this was, indeed a well-organized and careful study, among other issues it was far too short in patients’ follow-up to measure the impact of mammography on BC survival. The Annals papers, which caused so much controversy last year, relied heavily on old data and did not at attempt to examine the efficacy of digital mammograms.

What’s needed, still, for public health policy in the U.S. is evidence regarding the long-term outcomes after digital mammography performed in FDA-regulated, modern facilities by skilled, board-certified radiologists applied every other year in women who are over the age of 40 in the context of modern, adjuvant treatments and current pathology methods.

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As for the analysis by G. Kolata in the Times, where she wrote:

“…it indicates that improved treatments with hormonal therapy and other targeted drugs may have, in a way, washed out most of mammography’s benefits by making it less important to find cancers when they are too small to feel.”

I’d say the opposite is true:

It’s precisely because there are effective treatments for early-stage disease that it’s worth finding breast cancer by mammography. Otherwise, what would be the point?

Metastatic breast cancer is quite costly to treat and, even with some available targeted therapies, remains incurable.  Despite so many advances in treating early-stage BC, the survival rate at 5 years is under 25 percent for women with Stage IV disease.

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*abstract available, otherwise by subscription

**mortality rates: per 100,000 person-years

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Stepping Back, and Thinking Forward to October

Before jumping into the raring-to-go, already re-sparked debate on the value of breast cancer screening, or not, I thought I’d step back today and consider the background of what I won’t call the “mammography wars.”

So here’s the first point on this subject: happily, it’s not a war. This is about medical progress, or lack of progress, and what may or may not spare women morbidity (what doctors and stats types call illness) and mortality (death). This is not a battle by any sane measure.

The discussion should be civil and fair, ideally without assumptions and bias. (Of course it’s impossible for me to be unbiased on this subject – I am a trained oncologist, I’ve treated women with breast cancer who responded to chemotherapy drugs and witnessed their subsequent well-being, and I’ve seen women with metastatic breast cancer who died with disease eating through their bones and brains. And I had breast cancer, and was lucky that mine was found in an early stage. So far am well in that respect, eight years ago next month and counting -)

So I have bias, yes, but my second point is that we all do. Every journalist does, whether or not they’re up front about their life-experiences and community background, and so does every medical researcher and public health official who authors a paper and is not a robot. We delineate stories, analyze and represent data based on points we want to make and, in some medical journals – even for some trials that aren’t funded by drug companies – publish to serve academic, career or even what we think are idealistic, cost-saving, pain or procedure-sparing often high-minded goals.

Data can be very tricky to sort out and among.

The problems with mammography studies, as partly-detailed in the current NEJM paper, is that it’s considered impossible to do a controlled, randomized trial in which half of the women undergo screening and half don’t. (I might argue this assumption; now, that so many women and doctors are questioning the merit of mammography, maybe we could do a truly randomized trial involving a few thousand women in the U.S.) This issue relates to the important topic of ethics and real-life dilemmas oncologists face when they set up studies for evaluation or treatment of humans some of whom are likely to die.

But before we delve into the details of this study, and next month (October), what I hope is that we’ll keep some facts in mind:

The National Cancer Institute estimates that 40,000 women will die of breast cancer this year in the U.S. There’s been dramatic progress in how we manage this once-dreaded condition: prior to 1926, fewer than 20 percent of women survived for 5 years after diagnosis. By 1950, the overall 5-year survival rate among Caucasian women with breast cancer was 60 percent. Now, the overall 5-year survival rate is around 91 percent.

A question central to today’s discussion – which does at least acknowledge the decline in breast cancer mortality – is the extent to which mammography is responsible for this trend, as opposed to other factors such as increased awareness about cancer, better cancer treatments and other variables.

What concerns me is the tone of the debate on mammography, that it shouldn’t subtly or not-so-subtly, denigrate women’s valid concerns about their health. The quote with which today’s front-page story ends is this: “I think we have to respect what women want to do.” The way the story is framed insinuates that a decision to undergo mammography is based on something other than reason.

To be clear: this is not about what women want. It’s not about emotional turmoil, comfort, stress or people’s feelings. It’s about the efficacy of state-of-the art mammograms and whether or not those, when taken by skilled, well-trained radiologists in carefully-regulated modern facilities save women’s lives, at a reasonable cost (however we might calculate that) and reduce illness by detecting breast cancer in its early stages.

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