News, Information, Facts and Fiction

This morning I was in the gym, half-watching CNN as I did my usual exercises. Mathew Chance, a senior international correspondent based in Moscow, recapped the horrific scene involving explosions at two metro stations at the peak of rush hour. Chance reported that the bombers were both women. Most of the other facts surrounding the tragedy remain uncertain, he said. John Roberts, one of the CNN hosts, asked about any claims of responsibility for the terrorist attacks.

“Well, in fact, we had some information earlier today,” Chance responded. “…there had been a claim of responsibility…But that information appears to be incorrect.”

Wow!  Now, there’s an AM Fix.

Can information be wrong? Of course it can, we all know. There’s good evidence for this in my medical textbooks, among other reliable sources.

Lately, and especially since I started this blog, I’ve been thinking a lot about the nature of information – how we define it, how and if it might be distinguished from data, and what separates information and opinion.

“Information is the lifeblood of modern medicine,” wrote Dr. David Blumenthal in a carefully-designated “perspective” piece in the February 4 issue of the New England Journal of Medicine. He continued:

Health information technology (HIT) is destined to be its circulatory system. Without that system, neither individual physicians nor health care institutions can perform at their best or deliver the highest-quality care, any more than an Olympian could excel with a failing heart…

OK, so information needs to get around. It’s kind-of like blood; we can’t thrive without it. We won’t win any gold medals in health-care delivery before implementing the Health Information Technology for Economic and Clinical Health (HITECH) Act.

I agree on the essentialness of information in medical practice and decision-making. But that brings us back to the crucial issue of its nature – how people, doctors, scientists, news reporters or anyone, literate or otherwise, can tell if something’s true or untrue.

Last year in journalism school at Columbia University I took a course called “Evidence and Inference.” We went as far back as Plato’s cave, and as far forward as the New York Times’ 2002 reporting on possible evidence for weapons of mass destruction in Iraq. The point of the exercise, in sum, was that it’s sometimes hard, even for inquisitive journalists, scholars and scientists, to tell fact from fiction.

(Rest assured, I didn’t need a graduate course at Columbia to learn that much, although I did enjoy going back to school.)

Last week’s cover story in the Economist, on “Spin, Science and Climate Change,” drew my attention to some parallels between the Climategate controversy and distrust regarding other areas of scientific and medical knowledge. In a briefing within, the author or authors write:

…In any complex scientific picture of the world there will be gaps, misperceptions and mistakes. Whether your impression is dominated by the whole or the holes will depend on your attitude to the project at hand. You might say that some see a jigsaw where others see a house of cards. Jigsaw types have in mind an overall picture and are open to bits being taken out, moved around or abandoned should they not fit. Those who see houses of cards think that if any piece is removed, the whole lot falls down. When it comes to climate, academic scientists are jigsaw types, dissenters from their view house-of-cards-ists.

The authors go on to consider some ramifications of a consensus effect. (There’s an interesting discussion on this, which relates to a herding effect, in a recent post by Respectful Insolence).  Meanwhile, house-of-card-ists, dubbed doubters, emphasize errors from confirmational bias, or the tendency of some people to select evidence that agrees with their outlook.

There’s far more to consider on this subject – how we perceive and represent information – than I might possibly include in today’s post. So let’s just call this the start of a long conversation.

Getting back to medical lessons – the problem is that most of us can’t possibly know what’s really right. (Yes, I mean doctors too.) Few know enough of the relevant and current facts, or even the necessary terms, to make decisions about, say, which therapy is best for Ewing’s sarcoma in a four-year-old child or whether a new drug for Parkinson’s is worth a try in your dad’s case. Even for those of us who know something about statistics, it’s tricky.

Ultimately, I think it comes down to a matter of trust in the people who provide us information. It’s about knowing your source, whether that’s Deep Throat, a person reporting from the street in Moscow early this morning, or your personal physician.

Well, it’s a holiday for me over the next few days. I’ll read some history first, and then some fiction.

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Another Erroneous Report on Breast Cancer Screening by Mammography

This week delivered another piece on the non-value of breast cancer screening by mammography. The report, published in the British Medical Journal (BMJ), would be minor except that it may add to the growing heap of erroneous data on the topic.

Disclosure: I’m a board-certified oncologist, I’ve had breast cancer and this issue matters to me more than it otherwise might. I’m biased, yes for sure. It’s also true that my position is particularly informed.

The new study is limited and confusing. My initial take was that it wasn’t post-worthy. But since it’s out there, mentioned and even deemed important by some friends and colleagues, I thought I should explain why I think it’s wrong:

What the authors tried to do was analyze trends in breast cancer mortality in relation to mammography’s availability in distinct regions of Denmark over several decades. Using Poisson regression, a form of statistical analysis, they looked for a correlation and found none. They concluded that they couldn’t detect a benefit of screening mammograms among Danish women who might benefit (see below).

Map of Denmark, CIA World Factbook (Wikimedia Commons)

Here’s what I think are the two most serious flaws in this observational study:

1. The investigators divided Denmark into two groups for analysis: one defined as the “screened area” comprises Copenhagen, where mammography’s been available since 1991, and Funen County, where it’s been available since 1993; and the “non-screened” area representing approximately 80% of the population – “the rest of the country.”

The problem is that Copenhagen is Denmark’s capital and Funen, the other main “screened” region, contains Odense, the country’s third largest city. It’s not reasonable to compare changes in breast cancer survival, with or without screening, between women living in mainly urban and mainly rural areas, as these regions can differ at baseline in education, diet, alcohol use, cigarette use, pollution levels and other potentially confounding variables. Also, the quality of medical care in itself can vary between urban and rural districts. Differences in availability of primary care, surgical and other supportive services can influence survival trends independently of breast cancer screening.

2. For purposes of their study, the authors split the Danish women into three age brackets: aged 35-54, “women who were too young to benefit from screening”; aged 55- 74, “women who could benefit from screening”; and 75 – 84, “older age groups.” This assumption, that women under the age of 55 can’t benefit from mammography, introduces circular reasoning into the study, right from the start.

—-

I’m not sure why the BMJ published this paper. I’m concerned, really, that it’s agenda-driven work. The authors state, up front, that their findings contradict those of 2005 report drawn from a distinct but overlapping data set, that mammography was associated with a 25% reduction in breast cancer deaths in Denmark.

What’s curious is that the researchers do in the end identify a possible small cancer mortality reduction among the younger women. In their words:

…We also note that in the age group too young to have benefited from screening, women experienced proportionately larger reductions in breast cancer mortality after screening was introduced than did those that could have benefited from screening.

This non-logic reflects the investigators’ erroneous presumption that there cannot be an advantage in women aged 35 – 55.

You can go ahead and examine this paper directly if you like. A true advantage of the BMJ is its open-access; it provides full text freely upon registration.

My take-home message: this flawed publication should not be used to support the contention that breast cancer screening by mammography is ineffective. Nor does it elucidate much about what’s happening with mammograms and breast cancer survival trends in Denmark.

What it does reveal, if anything, is how different researchers using similar but non-identical data sets can come up with conflicting results if they want to.

Finally, I’ll remind my readers that the mortality rate among women with breast cancer has declined dramatically in the U.S. since 1990 and in Copenhagen, when mammography became prevalent in those places. The studies published in November, 2009 in the Annals of Internal Medicine, on which the new U.S. Preventive Services Task Force recommendations were based, are limited by reasons I’ve outlined here and elsewhere.

Addendum (3/28/08) : typo correction, some links and map added on March 28 by ES.

Regret: I wish I could find a better public domain map source.

Request: if any readers happen to know something about Danish epidemiology, and how Copenhagen and Funen counties do or don’t differ from the rest of Denmark, please chime in!

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A New Nurse Jackie in Preview

Nurse Jackie’s back on TV tonight. I know this because when I logged on to the New York Times this morning her ad flashed right at me, front page and right center. She’s displayed prominently on Huff Po, vanishingly on Dictionary.com. With just a quick search I can’t find her anywhere in the Wall Street Journal. At the LA Times she takes over the screen.

Poster for Nurse Jackie, Season 2

(As an aside, on the shifting nature of medical information, most future readers of this post will not know for sure if what I’ve described about the present on-line positioning of these commercials for TV is true. The same happens in practicing medicine, when clear signs of disease – like abnormal crackles on a lung exam – can be fleeting, leaving no digital or even a film imprint, yet very real. So you’ll have to trust me, or take no value from this depiction.)

For the “facts” on Nurse Jackie you can find her on Showtime’s original website. There, the program promises to continue “its look deep inside the complicated heart and soul of a functioning addict, a loving wife, mother, and a first-class nurse.” I’m curious but must admit that last year I watched only part of one episode and didn’t return.

Back then I was turned off preemptively by the image of Edie Falco looking harsh, white-coated and unsmiling. The syringe and needle in her raised, gloved hand suggested a third finger, or at least that’s how it seemed as we drove past her image, repeatedly, on a giant billboard. That poster was enough for me. I’d spent too much time in hospitals in trust of innumerable nurses to want to see that side of health care delivery.

Also, I liked Edie as Carmela Soprano so much, then fresh in my memory. Why ruin it?

But today she beckons, half-smiling, an aura of pills and syringes above her head. Maybe she’s happy about the health care reform bill’s passage last night, but I don’t think she could have known about that when the photo was taken, or in her TV unreality world, that legislation matters. What’s clear is that Nurse Jackie looks warmer, tired maybe from her work. She’s appears ready to help someone, a stethoscope slung over her neck. Her right arm is raised, like in last year’s pose, but gentler, calmer. It’s no accident the poster heralds a “Holy Shift.”

Back to reality –

This morning I was listening to WNYC while reading the newspaper and eating my healthy breakfast. As I recall, according to a reporter assigned to assess the public’s and health care workers’ response to the health care reform bill among people on the street near Lenox Hill Hospital, in my neighborhood, one individual said she doesn’t really know what to expect from the changes because she gets most of her news from TV. I didn’t catch any more details – if she meant CNN, for example, or Fox or The View – and exactly how and why she found the source limiting.

One thing I did note in the Times, and also on the Kaiser Health News website, both of which provide excellent summaries of the hopefully-real health care changes to come, is that reform won’t even start to happen for the most part until 2014. Meanwhile grows an authentic addiction to the Internet, TV, radio and even some blurry advertisements for information on medicine that people can’t or don’t get elsewhere.

So I’m thinking I should watch Nurse Jackie tonight. Give it another try. Maybe I’ll learn something. And whatever did happen to the House of God?

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Peter Sings Colonoscopy

Hi Readers,

This new form of medical information outreach outweighed any other contenders for today’s post:

“When I had my colonoscopy I had a question on my mind.

Do we all look the same when the doctor sees us from behind?

Then I had the answer…

Peter Yarrow, starting The Colonoscopy Song

Am I pro- or con- colonoscopy for routine screening, you might wonder. Well, that depends.

Am I pro- or con- famous singers and other celebrities extolling the benefits of particular medical interventions? Well, that depends, too.

But I’m sure I prefer “Puff the Magic Dragon.” Also “Leaving on a Jet Plane” fills me with imperfect memories of 6th grade. (I don’t know much about the history of this song, but there is an older, grainier and harder-to-hear version on YouTube dating to March, 2008.)

Thanks Peter, for this unique verbalization of what some doctors might otherwise convey. Glad to see you singing, aging, smiling about something.

The CDC confirms that March is national colorectal cancer awareness month (NCCAM).

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A Small Study Offers Insight On Breast Cancer Patients’ Capacity and Eagerness to Participate in Medical Decisions

Last week the journal Cancer published a small but noteworthy report on women’s experiences with a relatively new breast cancer decision tool called Oncotype DX. This lab-based technology, which has not received FDA approval, takes a piece of a woman’s tumor and, by measuring expression of 21 genes within, estimates the likelihood, or risk, that her tumor will recur.

As things stand, women who receive a breast cancer diagnosis face difficult decisions regarding the extent of surgery they should undergo (see the New York Timesarticle of last week, with over 200 people weighing in on this ultra-sensitive matter). Once the surgeon has removed the tumor, choices about chemotherapy, hormone modifiers, radiation and other possible treatments challenge even the most informed patients among us.

Oncotype DX and similar techniques, like the FDA-approved Mammaprint, provide a more detailed molecular profile of a malignancy than what’s provided by conventional pathology labs. For women who have early-stage (non-metastatic), estrogen-receptor positive (ER+) breast cancer, this test provides risk-assessment that’s personalized, based on gene expression in the individual’s tumor.

Oncotype DX has been commercially available since 2004. The test “reads” three levels of risk for breast cancer recurrence at 10 years: “low” if the predicted recurrence rate is 11% or less, “intermediate” if the estimated rate falls between 12% and 21%, and high if the risk for recurrence is greater than 21%.

The investigators, based at the University of North Carolina, Chapel Hill, identified women eligible for the study who had an ER+, Stage I or II breast cancer removed and tested with the Oncotype Dx tool between 2004 and 2009. The researchers sent surveys to 104 women, of whom 78 completed the questionnaires and 77 could be evaluated for the study. They distributed the surveys between December, 2008 and May, 2009.

Several factors limit the study results including the small number of participants and  that the women were treated at just one medical center (where the oncologists were, presumably, familiar with Oncotype Dx). The patients were predominantly Caucasian, the majority had a college degree and most were financially secure (over 60% had a household income of greater than $60,000). Nonetheless, the report is interesting and, if confirmed by additional and larger studies involving other complex test results  in cancer treatment decisions, has potentially broad implications for communication between cancer patients and their oncologists.

Some highlights of the findings:

1. The overwhelming majority of women (97% of the survey respondents) recalled receiving information about the Oncotype Dx test from their oncologists. Two-thirds (67%) of those women reported they “understood a large amount or all” of what the doctors told them about their recurrence risk based on the test results.

2. Nearly all of the respondents (96%) said they would undergo the test if they had to decide again, and 95% would recommend the test to other women in the same situation.

3. Over three-quarters, 76% “found the test useful” because it determined whether there was a high chance their cancer would come back.

4. The majority of respondents (71%) accurately recalled their recurrence risk, indicating a number within 4% of that indicated by their personal test results.

Taken together, these findings support that a majority of women with breast cancer whose oncologists shared with them these genomic testing results, and who filled out the surveys, had good or excellent recall of the Oncotype Dx reports and felt that the test was helpful.

As an aside, the women were asked to rate their preferences regarding their personal input in medical decisions. Among the 77 respondents, 38% indicated they prefer to have an active role in medical decisions (meaning that they prefer to make their own decisions regardless of the doctor’s opinion or after “seriously considering” the doctor’s opinion) and 49% indicated they like a shared role, together with their doctors, in medical decisions. Only 13% of the women said they “prefer to leave the decision to <the> doctor.”

What’s striking is that among these women with early-stage breast cancer, 85% said they like to be involved in medical decisions. And 96% said they’d undergo the test again. Most of the women, despite imperfect if not frankly limited numeracy and literacy (as detailed in the publication) felt they understood the gist of what their doctors had told them, and indeed correctly answered questions about the likelihood of their tumor’s recurrence.

The results are encouraging, overall, about women’s eagerness to participate in medical decisions, and their capacity to benefit from information derived from complex, molecular tests.

*The capacity of Oncotype Dx to accurately assess the risk of breast cancer recurrence has been evaluated in previous, published studies including a 2004 publication in The New England Journal of Medicine and a 2006 paper in the Journal of Clinical Oncology. The test is manufactured, run and marketed by Genomic Health, based in Redwood City, California.

The National Cancer Institute lists an ongoing trial for women with hormone receptor-positive, node-positive breast cancer that includes evaluation with the Oncotype Dx tool.

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Other, Oral Targeted Cancer Treatments

Some of you may be wondering why I’m so fixated on oral, targeted therapies for cancer. In my last post I provided some information on nine cancer drugs aimed at cellular enzymes, or kinases.

I’m encouraged, first, by the rapidity of these drugs’ emergence: ten years ago, none of the kinase-blocking drugs were available except for a few in experimental trials; most received FDA approval only in the past five years. These are very new agents indeed.

Why I’m enthusiastic – I anticipate that within a few years from now, cancer patients will take “medication cocktails” for their tumors, much in the way people living with HIV use drug combinations to fend off infection.  Cancer will, in many circumstances now deemed incurable, be managed instead as a chronic disease.

Now I can complete my assignment – a list of current, oral FDA-approved targeted cancer therapies. As indicated previously, I’m not including hormonal treatments in this list. I considered oral drugs targeting kinases in the last post.

I should emphasize that I’m neither recommending nor advocating any particular drugs. Rather, my point is to demonstrate the evolution of the field, that so many new and varied types of cancer pills are available. I think this is the start of a new era in oncology with expanded treatment options for people with all kinds of malignancy.

Part II of FDA-approved Oral Targeted Treatments for Cancer (see also part I – on oral kinase inhibitors)

1. Zolinza (vorinostat) is FDA-approved for use in a few forms of lymphoma that are cutaneous T cell lymphoma (CTCL). These are non-Hodgkin’s lymphomas in which the malignant cells are T-lymphocytes infiltrating the skin.

How this agent works is by inhibiting histone deacetyalases. These enzymes act in the cell’s nucleus, or center, where lies the DNA strung out along chromosomes. It removes acetyl groups, small chemical structures, from histone proteins. The genetic material normally wraps around the histones, and the presence or absence of acetyl groups on histones affects how genes are turned on or off. (Merck, October 2006).

2. Targretin (bexarotene) comes in capsule and in gel forms. It’s a retinoid, a Vitamin A-like compound that binds retinoid X receptors. These receptors regulate gene expression in normal and malignant cells. The drug is FDA-approved for use in CTCL. (Ligand, now Eisai, December 1999).

3. Vesanoid (tretinoin) is a retinoid that binds retinoic acid receptors. This drug is approved by the FDA as part of the treatment regimen for a particular form of leukemia called acute promyelocytic leukemia (APL). The drug targets a retinoic acid receptor that’s abnormally produced in the malignant cells due to a disease-defining chromosomal switch involving the retinoic acid receptor alpha (Roche, and generic, 1995)

This list is derived, in part, from information on the National Cancer Institute website on targeted cancer therapies, supplemented by other public-access resources on the relevant drugs and molecules as I’ve indicated with relevant links.

Some comments:

In this review, I note that some drugs that are not conceptually distinct from conventional chemotherapy or hormonal treatment appear to be marketed as “targeted” cancer treatment. My concern is that some companies are using this term, which implies a scalpel-like effectiveness and selectivity, to sell drugs to patients and oncologists (who may not all be up on their kinases) regardless of the drugs’ real specificity or lack thereof.

Given that all cancer drugs are designed, in principle, to kill malignant cells without killing the person who has cancer, we might consider all anti-tumor drugs as “targeted therapy.” But I don’t think that would be reasonable or helpful to patients and physicians who are trying to distinguish among treatment options.

In my opinion, the “targeted” term should apply only to drugs that impede troublesome molecules that act up particularly in the malignant cells, such as the bcr-abl tyrosine kinase mentioned in the last post, or the altered retinoic acid receptor that’s implicated in APL, as considered above.

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Some Targeted Therapies for Cancer Come as Pills

This post, on FDA-approved small-molecule targeted therapies for cancer, seems like a homework assignment of sorts. But really I found it a useful exercise and hope some readers might find it so, too. In searching the Web, I found remarkably little on this that’s public-domain, comprehensive and organized. In fact, there seems to be a lot of confusion about what these drugs are and how these differ from conventional, cytotoxic chemotherapies.

Some historical perspective:

Before 1970, few people received chemotherapy. Even with a cancer diagnosis, most treatments were surgical and radiation-based. A few older agents, chemotherapy pills such as chlorambucil and melphalan were given by mouth. From 1970 until 2000 (more or less), the thrust of most new cancer treatments involved stronger and sometimes more effective combination chemotherapy regimens. Almost all of those new treatments were given by intravenous (IV).

One point here that’s relevant to health care reform and the current debate on physician payments is that as things stand, oncologists and medical centers make money by giving IV infusions. Each treatment is billed as a procedure, apart from the cost of the medication in itself. So if patients can take a drug without a catheter, it might be less costly – there’s no nurse to hire, no catheter to purchase and insert and there’s no billing for an infusion per se.

And there’s less cost to the patient in terms of hassle and some untoward effects of IV treatment. With oral drugs (capsules, pills or tablets – anything taken by mouth) there’s no need to go to the doctor’s office or medical center every week or every other week, or even daily as is prescribed for some chemo regimens. There’s no need to have one’s arms shot up or a permanent, dangling catheter inserted. There’s no attendant risk for infection from an IV or semi-permanent catheter.

Reality check: most effective cancer drugs are not available in pill form, and for the most part these targeted treatments are in their infancy. But their number is expanding, so much so that most of the cancer pills I’m about to list have been approved only in the past five years.

Take further note: these are toxic drugs. Targeted therapies are designed, in principle, to kill malignant cells while leaving normal, healthy cells alone. Unfortunately, the effects of the medications listed below are broader than would be ideal. In general, these pills take aim at molecules that are over-active in cancer cells. But most of the affected enzymes are present in regular, healthy cells, too.

Here’s a list of small-molecule, oral drugs that target cancer cell enzymes and have received Food and Drug Administration approval prior to March 9, 2010, in order of approval:

1. Gleevec (imatinib, STI-571) was the first drug in this class to receive FDA approval. It counteracts an abnormal enzyme, a tyrosine kinase, that’s active in chronic myelogenous leukemia (CML) cells. The malignant tyrosine kinase, bcr-abl, arises in most cases from a chromosomal switch, called the Philadelphia Chromosome.

It turns out this drug works, also, against another tyrosine kinase, one related to a cell surface receptor protein called c-kit that’s mutated and activated in many Gastrointestinal Stromal Tumors (GIST). In 2002 the FDA approved use of Gleevec for GIST tumors in “c-kit+” tumors, meaning GIST cancers in which the c-kit receptor is mutated.

Since then the drug’s been approved for additional uses, only in some and quite specific circumstances, for adults with acute lymphoblastic leukemia (ALL) in which the malignant cells harbor the Philadelphia Chromosome (Ph+) and for some patients with other, mainly rare blood disorders in which particular genetic changes are established. (Novartis, May 2001)

2. Tarceva (erlotinib). This drug is also a tyrosine kinase inhibitor and is thought to act primarily by blocking growth signals of the Epidermal Growth Factor Receptor (EGFR). The drug was initially approved for use in some patients with non-small cell lung cancer and, more recently, for patients with pancreatic cancer. (Genentech, November 2004)

(Here I should mention Iressa (gefitinib) that was approved by the FDA early on for treatment of patients with advanced non-small lung cancer. Like Tarceva, Iressa has activity against EGFR-linked kinase activity and growth signals. The drug is no longer approved for most patients. AstraZeneca, 2003)

3. Sprycel (dasatinib). Like Gleevec, this targeted therapy blocks the bcr-abl tyrosine kinase activity in CML. The FDA approved this medication for CML patients whose disease progressed while on Gleevec (Gleevec-refractory CML) and for some adults with ALL in whom the malignant cells are Ph+. (Bristol-Myers Squibb, June 2006)

4. Sutent (sunitinib). Sutent is approved for use in metastatic kidney cancer and in GIST tumors that have progressed during treatment with Gleevec. It’s a fairly broad-acting tyrosine kinase inhibitor. (Pfizer, January 2006)

5. Tykerb (lapatinib). Tykerb is the only small-molecule drug that’s FDA-approved for use in some breast cancer cases. It blocks growth signals through Her2 (Her2/neu), a receptor tyrosine kinase that’s present on the surface of some breast cancer cells. The drug is approved for patients with metastatic breast cancer that’s Her2+ (meaning that the malignant cells display this molecule) and when it’s given in combination with Xeloda (capecitabine, an oral version of an otherwise conventional chemotherapy).

In January of 2010, the FDA granted accelerated approval of Tykerb in conjunction with Femara (letrozole, a hormonal therapy) in some patients with metastatic, Her2+ breast cancer in which the cells also express estrogen and/or progesterone receptors. (GlaxoSmithKline, March 2007)

6. Tasigna (nilotinib). This is the latest drug to tackle the bcr-abl tyrosine kinase activity in CML. It’s approved for adults with CML who have failed at least one regimen containing Gleevec. (Novartis, October 2007).

7. Nexavar (sorafenib). This therapy may not be targeted in the truest sense because its activity is so broad. It blocks receptor-linked tyrosine kinases such as those associated with Vascular Endothelial Growth Factor Receptor (VEGF-R) and Platelet Derived Growth Factor Receptor (PDGF-R). It inhibits other types of signaling enzymes inside cells, such as Raf-associated serine-threonine kinases.

The FDA has approved this drug for two groups of patients: those with advanced renal cell (kidney) cancer and those with liver tumors that can’t be removed by surgery.  (Bayer, November 2007)

8. Afinitor (everolimus) is in a slightly different class of drugs, in that it blocks mTOR (mammalian target of rapamycin, another sort of cellular enzyme). This drug is approved for use in patients with metastatic kidney cancer whose disease has progressed after Sutent and Nexavar. (Novartis, March 2009)

9. Votrient (pazopanib) blocks numerous tyrosine kinases and is the latest FDA-approved drug in this class. It’s approved for patients with advanced renal cell (kidney) cancer. (GlaxoSmithKline, October 2009)

Note to readers: other, oral targeted therapies are available that act by different sorts of mechanisms. I will cover those separately.

Several websites provide more information on so-called targeted therapies for cancer, including new intravenous treatments, monoclonal antibodies and some drugs that act by distinct mechanisms. Some of the sites I recommend for this topic include the National Cancer Institute and the American Society of Clinical Oncology’s Cancer.Net.

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Considering Targeted Therapies For Cancer

I first heard about STI-571 (Gleevec, a targeted cancer therapy) from a cab driver in New Orleans in 1999. “Some of the doctors told me there’s a new cure for leukemia,” he mentioned.

We were stuck in traffic somewhere between the airport and the now-unforgettable convention center. His prior fare, a group of physicians in town for the American Society of Hematology’s annual meeting, spoke highly of a promising new treatment. It seemed as if he wanted my opinion, to know if it were true. Indeed, Dr. Brian Druker gave a landmark plenary presentation on the effectiveness of STI-571 in patients with chronic myelogenous leukemia (CML) at the conference. I was aware of the study findings.

“Yes,” I said. “There is a new drug for leukemia.”

Since then, oncologists’ enthusiasm for targeted therapies – medications designed to fight cancer directly and specifically – has largely held. But the public’s enthusiasm is less apparent. Perhaps that’s because many people are unaware of these new drugs’ potential, or they’re put off by their hefty price tags.

Today Bloomberg News features a detailed and, I think, thoughtful story on the high cost of Sutent (sunitinib malate). This “miracle drug,” similar in many ways to Gleevec, typifies the problem of developing and providing new targeted therapies for patients with cancer. Sutent costs as much as $200 per pill, amounting to almost $50,000 per year for those who benefit. But the drug helps only a fraction of the patients for whom it’s prescribed.

So I thought I might review targeted cancer therapies, the costs-benefits issue being real and relevant. N.B.: addressing these drugs’ relative merits, effectiveness and side effects is beyond the scope of this blog. Rather, I’ll try to provide a simple framework for understanding these drugs, some information on the distinct types of new treatments and how these might work to fight cancer.

First, the framework: although many news articles consider targeted therapies together, I’d divide these in three main classes:

1. Enzyme Inhibitors. These drugs, most of which are available as pills, are designed to inhibit specific, abnormally-active signaling molecules in cancer cells. Gleevec was the first of this sort of therapy approved by the Food and Drug Administration.

2. Monoclonal antibodies. Antibodies are proteins that healthy immune cells, called B lymphocytes, generate in response to infection. Whether medicinal or native, these complex molecules circulate in the plasma component of the bloodstream. What matters to many patients is this: antibodies are given by infusion (intravenous, IV) or, rarely, by injection. Herceptin (trastuzumab) is a good example of a targeted, monoclonal antibody treatment for breast cancer.

3. Hormonal treatments. These, for the most part, target estrogen receptors in breast cancer. (I am not convinced that these are truly “targeted therapies,” but as the NCI website lists these as such, I’ll go with the flow. Femara (letrozole), a drug that reduces estrogen and other steroid levels, falls in this class.

In a forthcoming post I’ll review the small molecule-type targeted therapies for cancer that have been approved by the FDA. After that, the monoclonals. If I’m feeling brave, I may cover hormonal treatments for breast and prostate cancer.

As for traveling in New Orleans, I hope to get back there soon enough. If I do take a cab there, I wonder what news the driver will report.

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The High Cost of Food-Borne Illness, and Some Steps To Avoid These in Your Home

A new report from the “Make our Food Safe” project, based at Georgetown University, makes clear that food-borne illnesses – from bacteria, parasites and a few viruses – are ever-present and costly.

The study, authored by Robert Scharff and funded by the Pew Charitable Trusts, finds that food-borne illnesses tally nearly $152 billion per year. This measure includes some subjectively-measured expenses like pain, suffering and missed work. Even without those, the toll registers above $100 billion – a huge sum, either way.

The main culprits are familiar: salmonella, that commonly reside in uncooked poultry and eggs, sometimes lace vegetables and lately tinge peanut butter, causes some 1.5 million illnesses per year. E coli 0157:H7, a dangerous bacterial strain that turns up disproportionately in ground beef and recently on fresh spinach leaves, is less prevalent but more often damaging; it takes kidneys and sometimes lives.

The Centers for Disease Control (CDC) provides a lot of useful information on its website regarding food safety.

As a doctor, and as a mom, I see this report as a nudge to be mindful in our kitchens, to follow what should be obvious advice from a collectively-conjured grandmother.

1. Before starting to prepare food, wash your hands with soap. Do this again after handling any raw meat, eggs or fish.

2. Keep raw meat, especially poultry, apart from any surfaces where cooked food is placed, stored or served. Cook chicken thoroughly, always.

3. The same goes for eggs.

4. Salad is one of the most dangerous foods we eat. It’s loaded with dirt from the ground. To wash lettuce for salad, let water pass over each leaf and rinse, fully, at least three times. Tomatoes should be handled similarly. Carefully peel carrots, cucumbers and most other vegetables if they’re to be eaten raw.

5. Unpeeled fruits like grapes and berries are handled like vegetables for salad; they’re washed at least three times.

(N.B.: this method of aggressively washing produce 3x is hardly full-proof; it reduces the amount of dirt on the surface of fruits and vegetables but does not completely eliminate germs.)

6. It’s hard, if not impossible, to adequately wash leeks, scallions, potatoes, mushrooms and most other vegetables. These are best washed and then cooked by sautéing, roasting, steaming or another method. The point is to cook with heat – of sufficient duration and intensity – to kill most bacteria, parasites and other germs.

7. Hygiene matters, especially around the kitchen and eating area. It’s a good idea to wipe down the table and kitchen counter surface after each meal.

These are just some suggestions for ways we can reduce the likelihood of being affected by food-borne illness at home. For people whose immune systems are compromised, such as those undergoing chemotherapy, with HIV and some other conditions, there’s reason to take extra care with salad and raw produce.

Knowing what we do about food-borne illnesses can influence choices we make when we eat outside of our homes. For example, in a restaurant, I’ll eat cooked but not raw spinach, because I know how difficult it is to properly wash that vegetable. If I order a burger, I’ll ask that it be very well-done, to minimize the risk from e. coli.

When traveling, I sometimes avoid uncooked fruits and vegetables entirely – but that’s another story.

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MedlinePlus, Now More Than Ever

Last week, ABC announced drastic cuts for its newsroom staff. The situation is similar at CBS, which in early February reduced its news-gathering personnel. These pull-backs by the major networks, paralleled by lessening or flat-out elimination of newspapers, will boost the number of people who check the Internet for medical news.

Two recent studies, from the Pew Center’s Internet & American Life Project and the CDC’s National Center for Health Statistics, confirm that most Americans are going on-line for health information. Compounding this effect, in all likelihood, are the uninsured, those reluctant to fork out hefty co-pays and some who are unable to dole out a deductible before they see a doctor.

Bottom line: the role of Internet-based health resources is likely to expand over the next decade. We need to know what’s out there –

We should start with MedlinePlus, a virtual superstore of free medical information. Co-sponsored by the National Library of Medicine (NLM) and the National Institutes of Health (NIH), this site is comprehensive and relatively clear of commercial bias. (There are significant exceptions, see below). It’s a useful origin for most any health-related search.

MedlinePlus covers more than 800 topics in English, 500 in Spanish and selective information in over 45 languages – you can read about anemia in Bosnian, hand hygiene in Creole or viral hepatitis in the Hmong language.

The site includes a medical dictionary, an encyclopedia (provided by A.D.A.M., a health education company that’s traded on the NASDAQ, ADAM), a compendium of drugs, supplements and herbs (put forth by the American Society of Health-System Pharmacists), a database on herbal remedies from Natural Standard, and some 165 interactive health tutorials.

There’s a direct link to the original on-line database that doctors used for decades, Medline/PubMed. This professional reference encompasses over 16 million articles published in more than 5000 scientific and medical journals. For the most part it’s a well-organized list of titles and abstracts, or summaries, of biomedical papers. A growing proportion of the articles are available in their entirety, and the abstracts can sometimes provide helpful clues in a medical search.

Another key connection is to ClinicalTrials.gov, an NIH-sponsored registry of all federally-sponsored and many privately-funded clinical trials conducted in the United States and elsewhere. For cancer patients, this database is crucial; previously, only doctors searching for clinical trials could access a public database of experimental treatments. (I’ll cover this site in a separate, future post.)

MedlinePlus offers an extensive catalogue of surgical procedure videos. You can watch an abdominal hysterectomy, vasectomy reversal or open heart surgery if you choose. While the films can be helpful, perhaps, to some patients who are deliberating about a procedure, some of my non-physician friends have found them rather bloody. I have some reservations about this component of the MedlinePlus site, in that many of the videos are provided by community medical centers and, the films are provided by a commercial enterprise, ORlive.

In recent years the number of visitors to MedlinePlus has hovered over 10 million per month. In 2009, the site received hits from approximately 128 million distinct Web addresses.

Last year, I spoke with Robert Logan, Ph.D., of the Office of Communications at the National Library of Medicine. “We’ve hit some sort of tipping point,” he said. “The internet has eclipsed other health information sources.”

Despite the comprehensiveness of MedlinePlus, there’s work to be done, said Logan. Some particular areas he hopes to improve on include ethics, epidemiology and statistics. “It’s hard for people to look at numbers and make clinical decisions,” he said. “But that’s a serious weakness in all areas of medicine all over the world.”

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