This Week’s Triple, Tough Dose of Real Stories on Women with Cancer

Dear Readers,

It’s been a tough week on the breast cancer front.

Many in the community first learned that Ellen Moskowitz, a former leader at the Metastatic Breast Cancer Network (MBCN), died. Ellen was a funny, articulate woman who lived with MBC. When I interviewed her for an article on the value of a day designated to awareness about metastatic disease, she kept me laughing.

Robin Roberts, a co-host of Good Morning America who was treated for breast cancer less than 5 years ago, announced that she’ll be getting a bone marrow transplant for MDS. The blood condition is, in some cases, a complication of chemotherapy. I wrote a piece about this for the Atlantic Health. This unfortunate news reminds us an aspect of cancer treatment some of us would rather put out of our heads. The main message – which I hope came through editing – is that all cancer patients should take careful notes on their planned treatments and ask their doctors about the long-term consequences of therapy. Not all chemo is the same; the risks vary among regimens and doses. The reality is that some of us – patients and doctors – prefer not to think about late, long-term, possible effects of treatment, like secondary tumors, when there’s a life-threatening condition in hand. This doesn’t mean chemo isn’t the right choice. Often it is, but it should be weighed out, carefully.

Finally, we learned that Dr. Susan Love, a breast surgeon and professor at UCLA, and leader of an Army of Women, has leukemia. Dr. Susan Love’s Breast Book is a reference my friends and patients turned to in the 1990s, before the Internet was so loaded with cancer info, and many still do. She has, through that book and through her Foundation, besides through her work as a surgeon, helped an army of women to heal, and more.

My thoughts are with each of these remarkable women, and their loved ones, now.

ES

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EMILIA Trial: T-DM1 Appears Helpful in Women with Her2+ Metastatic Breast Cancer

This weekend the American Society of Clinical Oncology (ASCO), to which I belong, is holding its annual meeting in Chicago. Some of the biggest buzz has to do with a new breast cancer drug called T-DM1. ASCO just lifted embargo of the relevant abstract.

The new agent is a hybrid of an old monoclonal antibody, Herceptin, that’s chemically attached to DM1, a traditional kind of chemotherapy. The chemo part, DM1 – also known as emtansine – is manufactured by ImmunoGen. It’s derived from maytansine, a compound that binds tubulin, a protein critical for microtubule formation in dividing cells. According to the NCI website, this chemical, which has antibiotic properties, was extracted from an Ethiopian plant, Maytenus serrata.

T-DM1 was designed by linking the DM1 compound to the trastuzumab (Herceptin) antibody. Trastuzumab is old news in breast cancer. It binds a signaling molecule, Her2, that’s expressed at high levels in approximately 1 in 5 breast tumors. The FDA approved Herceptin for use in patients with metastatic, Her2+ breast cancer in 1998 and, for some women with localized, lymph node positive disease, in 2006. In this new, hybrid drug, the antibody works like a tagged, toxic messenger. In effect, the antibody delivers and inserts the chemo into the malignant cell, where it causes cell death.

The new data, from the Genentech-sponsored EMILIA trial, were presented today:

The Phase III study evaluated 991 women with metastatic breast cancer. All participants had tumors with high levels of Her2 (confirmed in a central pathology lab, for the trial). All had disease that progressed despite treatment with Herceptin and, in most cases, other drugs too. After randomization, 978 women received either of two treatments: the experimental agent, T-DM1, every 3 weeks, by intravenous infusion, or a combination of two pills, “XL” – Xeloda (capecitabine) and Tykerb (lapatinib). Median follow-up was just over 1 year – not bad for a study of MBC, but not great, either.

The big news is this: Among the patients who got the experimental drug, T-DM1, the median time until disease progressed was 9.6 month; for those who took the XL pill combination, it was 6.4 months. This different was statistically significant. Although a difference of 3 months may not sound like much – and isn’t – each regimen in the study held the women’s disease in check for over half a year.

It’s striking that T-DM1 was used as a single agent. Most chemotherapy drugs, like those for HIV, work best in combination; it could be that we’ll see more powerful results in a few years, once we learn how to optimally combine drugs for women with Her2+ breast cancer.

As far as overall survival, the initial results seem quite favorable. Among women on the study for 2 years, 65 percent were alive who received T-DM1; among those taking the XL regimen, 47 percent were alive at 2 years. (The statistical details for this comparison are not available; evidently it was of weak significance.) The problem is – if only a few patients were analyzed “so far out” on the survival curves, the difference observed between the two study arms might be random. Still, and independently of the comparison, survival of 65 percent at 2 years in this patient group is (sadly) impressive, especially if it comes by a single agent with comparatively few side effects.

The main T-DM1 toxicities were low platelets and abnormal liver function, which were, reportedly, reversible. The XL combination caused more toxicity, overall, including diarrhea, hand-foot syndrome and nausea.  A much greater fraction of women on the XL arm (53 and 27 percent, respectively for Xeloda and lapatinib) needed dose reductions, as compared to the T-DM1 (16 percent had dose reductions due to toxicity). Evidently hair loss isn’t an issue for women who get T-DM1, which is nice.

My main, initial concerns are two:

First, the study, though randomized, is not “blinded,” and can’t be.  It’s impossible for women who are getting an intravenous drug, and their doctors, not to know that they’re not on the pill study arm. Although there were independent evaluators of progressive disease, which is a far more subjective measurement than overall survival, progression free survival can be influenced by the doctors’ and patients’ knowing they’re getting the T-DM1. That said, the initial, observed difference in overall survival – a clear, objective measurement – is impressive.

If these trial results, published in abstract form, pan out, and the quality of patients’ lives is maintained, that’d be helpful to as many as 1 in 5 women with MBC. It is plausible that an antibody like Herceptin that targets the tumor cells could, in fact, “deliver” the chemo effectively into the cancer cells with relatively low toxicity. And if the women are feeling better, which is hard to know from an abstract, great.

My second concern is how this drug will mesh with others now available and in the pipeline for patients with Her2+ disease. In a December, 2010 editorial in the JCO, two clinical investigators wrote: “the unique aspect of T-DM1 is clearly its high clinical activity by itself, without the need of concomitant additional systemic chemotherapy.” They’re right. The question – as considered by those authors – is how T-DMI will be used in the context of expanding treatment options for women with Her2+ breast cancer. This is an expensive (price not yet known) monoclonal antibody-conjugate that’s necessarily given by infusion. Testing this drug against all the other current and up-and-coming alternatives, in varying combinations and doses, will be tricky. The trials alone will cost big bucks, besides toxicity and women’s lives.

These EMILIA results are promising for some women with MBC and, possibly, patients with other cancer forms in which Her2 is expressed. Unfortunately, it’s unlikely to help those women with breast cancer whose tumors that lack Her2+.

I’ll write soon about this new class of oncology drugs – antibodies conjugated to chemotherapies, as a group.

All for now,

ES

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New Article on Mammography Spawns False Hope That Breast Cancer is Not a Dangerous Disease

This week’s stir comes from the Annals of Internal Medicine. In a new analysis, researchers applied complex models to cancer screening and BC case data in Norway. They estimated how many women found to have invasive breast cancer are “overdiagnosed.” I cannot fathom why the editors of the Annals gave platform to such a convoluted and misleading medical report as Overdiagnosis of Invasive Breast Cancer Due to Mammography Screening: Results From the Norwegian Screening Program. But they did.

Here are a few of my concerns:

1. None of the four authors is an oncologist.

2. The researchers use mathematical arguments so complex to prove a point that Einstein would certainly, 100%, without a doubt, take issue with their model and proof.

3. “Overdiagnosis” is not defined in any clinical sense (such as the finding of a tumor in a woman that’s benign and doesn’t need treatment). Here, from the paper’s abstract:

The percentage of overdiagnosis was calculated by accounting for the expected decrease in incidence following cessation of screening after age 69 years (approach 1) and by comparing incidence in the current screening group with incidence among women 2 and 5 years older in the historical screening groups, accounting for average lead time (approach 2).

No joke: this is how “overdiagnosis” – the primary outcome of the study, is explained. After reading the paper in its entirety three times, I cannot find any better definition of overdiagnosis within the full text. Based on these manipulations, the researchers “find” an estimated rate of overdiagnosis attributable to mammography between 18 -25% by one method (model/approach 1) or 15-20% (model/approach 2).

4. The study includes a significant cohort of women between the ages of 70-79. Indolent tumors are more common in older women who, also, are more likely to die of other causes by virtue of their age. The analysis does not include women younger than 50 in its constructs.

5. My biggest concern is how this paper was broadcast – which, firstly, was too much.

Bloomberg News takes away this simple message in a headline:  “Breast Cancer Screening May Overdiagnose by Up to 25%.” Or, from the Boston Globe’s Daily Dose, “Mammograms may overdiagnose up to 1 in 4 breast cancers, Harvard study finds.” (Did they all get the same memo?)

The Washington Post’s Checkup offers some details: “Through complicated calculations, the researchers determined that between 15 percent and 25 percent of those diagnoses fell into the category of overdiagnosis — the detection of tumors that would have done no harm had they gone undetected.” But then the Post blows it with this commentary, a few paragraphs down:

The problem is that nobody yet knows how to predict which cancers can be left untreated and which will prove fatal if untreated. So for now the only viable approach is to regard all breast cancers as potentially fatal and treat them with surgery, radiation, chemotherapy or a combination of approaches, none of them pleasant options…

This is simply not true. Any pathologist or oncologist or breast cancer surgeon worth his or her education could tell you that not all breast cancers are the same. There’s a spectrum of disease. Some cases warrant more treatment than others, and some merit distinct forms of treatment, like Herceptin, or estrogen modulators, surgery alone…Very few forms of invasive breast cancer warrant no treatment unless the patient is so old that she is likely to die first of another condition, or the patient prefers to die of the disease. When and if they do arise, slow-growing subtypes should be evident to any well-trained, modern pathologist.

“Mammograms Spot Cancers That May Not Be Dangerous,” said WebMD, yesterday. This is feel-good news, and largely wishful.

A dangerous message, IMO.

Addendum, 4/15/12: The abstract of the Annals paper includes a definition of “overdiagnosis” that is absent in the body of the report: “…defined as the percentage of cases of cancer that would not have become clinically apparent in a woman’s lifetime without screening…” I acknowledge this is helpful, in understanding the study’s purpose. But this explanation does not clarify the study’s findings, which are abstract. The paper does not count or otherwise directly measure any clinical cases in which women’s tumors either didn’t grow or waned. It’s just a calculation. – ES

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Harsh Words, and Women’s Health at Risk

I’ll open with a confession –

Women’s health has never really been at the heart of ML. Your author has, historically, relegated subjects like normal menstruation, healthy pregnancy and reproduction and natural menopause to her gynecologist friends. Sure, I learned about the facts of life. I even studied them in med school and answered questions, some correctly, along the way. By now, I’ve lived through these real life-phases directly. But these topics never drew me. That’s changed now.

Women’s care – and lives, in effect – are jeopardized on three fronts:

First, on birth control. Last week the Senate narrowly tabled a move to limit insurers’ responsibility to cover contraception. The vote on the so-called “conscience” amendment was 51-48. What this tells us is that essentially half of that powerful group either agrees with limiting women’s access to birth control or sees it as dispensable in the context of political aims.

The very fact that the proposal reached the Senate floor is disturbing. Without access to birth control, women –  including teenagers, people with significant medical problems that can be exacerbated by pregnancy, those who can’t afford to feed another child, and some who are already troubled or otherwise might not be ready or prepared to have children – are much more likely to become pregnant. It shouldn’t take a doctor to articulate this obvious point, and I can’t understand why so many are silent on it, but since so few physicians and the AMA in particular hasn’t issued any statement on this, I’ll stick my neck out and say it clearly: Lack of contraception puts women and their conceivable future-kids at risk for health problems that could be avoided.

The language surrounding the amendment is problematic, besides. Who are the anti-birth control legislation-writers to imply that “conscience” is involved in withholding contraception, and not the other way around? It’s like the “pro-lifers” who’ve implied that the rest of us aren’t.

Second, on access to safe abortions. I respect that some people think it’s wrong to terminate a pregnancy. But I also know that plenty of women, especially young women, get pregnant who don’t want to be pregnant. Regardless of who’s “responsible” – and any reader of this blog knows I’m no sucker for finger-pointing and behavior blame games – the bottom line is that if abortions become out-of-reach, women will suffer hemorrhage, life-threatening infections, permanent infertility  and premature deaths.

Hard to know how many women had ill effects or died from botched abortions before January, 1973, when the Supreme Court issued its decision on Roe vs. Wade. Like most women of my generation, I know of those unfortunate outcomes only indirectly. Still, I can’t rid my brain of the scary, unclean place Natalie Wood visits with a wad of cash in the 1963 movie Love with the Proper Stranger, or the tragic outcome when actor Gael García Bernal takes his pregnant love to an abortionist in the film Crime of Padre Amaro, set a decade or so ago in Mexico. But the real scoop comes from older physicians and nurses, here and now. When I was in med school in the 1980s, they told me stories of women and girls showing up in the emergency room bleeding, pale… dead.

As outlined by editorialists and writers elsewhere, mergers of Catholic hospitals with other medical centers threaten to reduce or eliminate access to abortions in some rural areas. In states like Texas, the physical and emotional rigmarole to which pregnant women are subjected prior to an abortion – including mandatory listening to a description of the fetal organs and a discussion loaded make what might be a tough decision unbearable, especially if the woman lacks confidence.

Which leads me to the third point of vulnerability – that women should be able to obtain care without intimidation or emotional abuse.

When Rush Limbaugh spoke last week, he wasn’t just talking about one Georgetown Law student. He was speaking to and about millions of young women who are sexually active. He called them sluts and insinuated they are like prostitutes. Adding insult to verbal injury, he said he’d like to watch videos of the sex. You could say who cares, he’s just some right-winged showman blowing off steam and misogyny. But this is a man who speaks to conservative leaders and feeds ideas to many households in America. Scary that the Republican front-runners, men who would be President of the United States next year, didn’t call Rushbo out. Rather, they let it go. As they might your daughter’s health, or access to birth control, or to a safe abortion.

In this new climate of shame, it’s easy to imagine a girl in some communities might feel really, really bad about herself simply for being sexually active. Whether she’s 17 years in high school, or 21 years in college, or 25 and maybe a department store clerk – and possibly lonely or confused – she may be embarrassed to ask for birth control. The Scarlet C, Robert Walker aptly called it yesterday.

The paradox is that this kind of rough talk, posturing and in some states, puritanical law-making, make it more likely that a sexually active young woman will become pregnant. And if she does become so, now, she may delay seeing a doctor because she fears his or her moral judgment about her behavior. And that leads to less healthy outcomes, and more deaths – fetal and maternal.

This is a serious health issue. I wish more doctors would speak out about it.

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New Studies on Colon Cancer Screening by Colonoscopy and Fecal Blood Testing

Last week the NEJM published two major papers on screening for colon and rectal cancer. The most notable finding supports that colonoscopy – when done properly and not necessarily often – saves lives.

The NCI estimates that doctors will find over 103,000 colon and 40,000 rectal cancers, and the number of deaths will exceed 51,000 this year in the U.S. According to the ACS, colorectal cancer ranks third as a cause of cancer mortality in men and in women. In light of these numbers, the potential for screening to reduce deaths and costs of treating people with advanced disease is great.

Both analyses are unfortunately – almost dauntingly – complicated. An accompanying editorial, by Drs. M. Bretthauer and M. Kalager lends some perspective.

colon adenoma pathology, H&E stain, (Wiki Commons: "Nephron")

The first report comes from a group of researchers led by Ann Zauber, PhD, a biostatistician at MSKCC. This team examined long-term outcomes among 2602 adults who had adenomatous polyps removed between 1980 and 1990, followed by colonoscopy recommended at varying intervals in a trial. With a median follow-up of 15.8 years, there were only 12 deaths from colon cancer in the study population – essentially half the number expected by comparison with SEER data.

The main limitations I see in this report are two. First, what might be considered a good thing – the high compliance rate: 81% of those with adenomas underwent some follow-up colonoscopy. And second – along a similar vein – that the colonoscopies were performed by highly-trained physicians at academic centers in a trial that mandated a certain degree of thoroughness and quality. Some criticism of the work is that the findings won’t translate to the community at large, as mentioned in the editorial and in the paper itself. That’s because some “real world” gastroenterologists don’t perform the procedure so carefully. Apart from the trial, many people are genuinely hesitant about having colonoscopy out of concern about its unpleasantness and also costs. Compliance with colonoscopy recommendations runs low.

These are valid concerns. But they don’t abrogate the value of the procedure. Rather, they point to the need for rigorous training of doctors who do colonoscopy, for close monitoring of facilities where it’s done (and in path labs, where the specimens are evaluated), and for insurance or a national health plan to enable patients, if they choose, to have this potentially life-saving screening test covered.

The second study, from a group in Spain, examined the relative merits of checking stool samples for blood every two years vs. colonoscopy every ten years in over 50,000 people. The preliminary finding – after just one “round” of colonoscopy in those assigned to that trial arm, is that a higher proportion complied with fecal blood testing than with colonoscopy. Among those who underwent colonoscopy, cancers and adenomas were found in a greater fraction. But the absolute number of cancers detected was essentially the same in each group, because more people assigned to fecal screening completed the task.

My take from these reports, combined, is that periodic colonoscopy has the potential to halve the number of deaths from colon cancer in the general population. But it’s an unpleasant, invasive and expensive test that does carry some risks. The quality of the test – both in terms of its thoroughness and risk of complication – would depend, in part, on the training and experience of the doctor who performs the test. So, as with mammography, I favor heavy regulation and careful certification of physicians who perform these procedures.

As to how colonoscopy relates to fecal blood testing as a screening method at the population level, and the optimal start and frequency of either test, those remain uncertain. Dr. Zauber, it turns out, heads the NCI-funded National Colonoscopy Study. This ongoing work will, hopefully, shed light on how testing for blood in stool samples compares with colonoscopy in colon cancer screening and, ultimately, costs and mortality from late-stage disease.

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Counterfeit Drugs, A New Concern for Patients

This week the FDA issued an alert about fake Avastin. The real drug is a Genentech-manufactured monoclonal antibody prescribed to some cancer patients. Counterfeit vials were sold and distributed to more than a dozen offices and medical treatment facilities in the U.S. This event, which seems to have affected a small number of patients and practices, should sound a big alarm.

Even the most empowered patient – one who’s read up on his drug regimen, and engaged with his physician about what and how much he wants to receive, and visited several doctors for second opinions and went on-line to discuss treatment options with other patients and possibly some experts – can’t know, for sure, exactly what’s in the bag attached to his IV pole.

Counterfeit Avastin (images from FDA)

Scary because patients are so vulnerable –

The problem is this. If you’re sick and really need care, at some point you have to trust that what you’re getting, whether it’s a dose of an antibiotic, or a hit of radiation to a bone met, or a drug thinner, is what it’s supposed to be. If vials are mislabeled, or machines wrongly calibrated, the error might be impossible to detect until side effects appear. If you’re getting a hoax of a cancer drug in combination with other chemo, and it might or might not work in your case, and its side effects – typically affecting just a small percent of recipients – are in a black box, it could be really hard to know you’re not getting the right stuff.

What this means for providers is that your patients are counting on you to dot the i’s. Be careful. Know your sources. Triple-check everything.

The bigger picture – and this falls into a pattern of a profit motive interfering with good care – is that pharmacists and doctors and nurses need time to do their work carefully. They need to get rest, so that they’re not working robotically, and so that they don’t assume that someone else has already checked what they haven’t. And whoever is buying medications or supplies for a medical center, let’s hope they’re not cutting shady deals.

This issue may be broader than is known, now. The ongoing chemo shortage might make a practice “hungry” for drugs. And with so many uninsured, some patients may seek treatments from less-than-reputable infusion givers. The black market, presumably, includes drugs besides Avastin.

If I were receiving an infusion today, like chemo or anesthesia or an infusion of an antibody for Crohn’s disease, I’d worry a little bit extra. I mean, who will check every single vial and label and box? Think of the average hospital patient, and how much stuff they receive in an ordinary day – including IV fluids that might be contaminated with bacteria.

It’s scary because of the loss of control. This circumstance might be inherent to being a patient – in being a true patient and not a “consumer.”

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Oh, No Methotrexate!

structure of MTX (PubChem; NCBI)

I was astonished to learn that methotrexate supplies are running short. This chemotherapy may soon be unavailable to patients who need it. And it’s not just kids with leukemia, as the Times story highlights effectively.

Methotrexate is an old, bread-and-butter cancer kind of drug, a basic ingredient in standard regimens for many tumor types. I’ve personally administered this medication to patients with breast cancer, lymphoma, leukemia, head and neck tumors, ovarian cancer, colon cancer and people whose tumor cells spread to the brain. Doctors prescribe this drug, also, in a few non-malignant conditions, like rheumatoid arthritis.

Methotrexate has been used in cancer wards for over 50 years. And like other beyond-patent meds, it’s become less profitable to manufacture MTX compared to much costlier new agents. Hard to perceive this shortage as anything but a tragedy – that the business of health care renders valuable, inexpensive drugs out of reach.

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Study Finds Wide Variation in Reoperation Rates after Lumpectomy for Breast Cancer

The Feb 1 issue of JAMA includes a major report on the practice of lumpectomy in the U.S. The study examined what happened to 2,206 women at four medical centers who opted for breast-conserving surgery at the time of breast cancer diagnosis. The main finding was that after lumpectomy, nearly one in four women had another operation to remove cancerous cells in the breast. Among all the breast cancer patients who began with a lumpectomy, 8.5% wound up with a mastectomy.

These are staggeringly high rates of re-operation in women who opted for small procedures to begin with. Many of the women who had additional procedures did so for concern over having “clean margins” – that upon removal of a tumor, the edges of the specimen don’t reveal malignant cells. Re-excision for patients with negative margins varied by hospital; at one medical center the re-excision rate was 1.7%, at another it was 20.9%. Analysis by surgeon revealed huge variation, with re-excision rates ranging between 0 and 70%. The incidence of positive margins was 14%.

What further clouds the story is that among women who did have positive margins, meaning that cancerous cells were evident along the edge of the lump removed, nearly 15% didn’t have a second procedure. The big picture is that there was little pattern – or reason evident, at least at the collective level – for the surgeries and decisions to re-operate after lumpectomy for breast cancer.

The study, funded by the NIH, was sufficiently large to merit concern. It involved careful chart and pathology review of the specimens through a consortium of four medical centers around the country: the University of Vermont, Kaiser Permanente Colorado, Group Health in Washington State and the Marshfield Clinic in Wisconsin. And it reflects current practice; the surgeries took place between 2003 and 2008.

Lumpectomy is a very common procedure – and a significant issue, in terms of costs, and risks, and decisions women make every day upon receiving a new BC diagnosis. An estimated 60-70% of newly-diagnosed breast cancer patients choose breast-conserving surgery. So we’re talking about 160,000 or so lumpectomies per year in the U.S. (very approximate, ES: 2/3 of 240,000 new BC cases).  The variable results affect cosmetic outcome – the very reason many women choose lumpectomy to begin with and, potentially, the rate of BC recurrence.

The authors discuss: “Our finding…suggests that patients under similar clinical conditions are likely to undergo reexcision based on the treating surgeon and not just the clinical characteristics.” They offer possible explanations, including differences in surgical training, surgeons’ confidence in their operative techniques, how tumors are assessed in the operating room, and variation in how pathologists review specimens and “call” the margins positive or negative.

All of this meshes with my experience – knowing women who’ve had breast-conserving surgery and then got mixed information about the results and what to do next. You’d think lumpectomy would be a standard procedure by now, and that decisions about what to do after the procedure, surgically speaking (let alone decisions about chemo, hormonal treatments and radiation) would be straightforward in most cases.

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Cyberchondria Rising – What is the Term’s Meaning and History?

Yesterday the AMA news informed me that cyberchondria is on the rise. So it’s a good moment to consider the term’s meaning and history.

Cyberchondria is an unfounded health concern that develops upon searching the Internet for information about symptoms or a disease. A cyberchondriac is someone who surfs the Web about a medical problem and worries about it unduly.

Through Wikipedia, I located what might be the first reference to cyberchondria in a medical journal: a 2003 article in the Journal of Neurology, Neurosurgery, and Psychiatry. A section on the new diagnosis starts like this: “Although not yet in the Oxford English Dictionary, the word ‘cyberchondria’ has been coined to describe the excessive use of internet health sites to fuel health anxiety.” That academic report links back to a 2001 story in the Independent, “Are you a Cyberchondriac?”

Two Microsoft researchers, Ryen White and Eric Horvitz, authored a “classic” paper: Cyberchondria: Studies of the Escalation of Medical Concerns in Web Search. This academic paper, published in 2009, reviews the history of cyberchondria and results of a survey on Internet searches and anxiety.

Interesting that the term – coined in a newspaper story and evaluated largely by IT experts – has entered the medical lexicon. I wonder how the American Psychiatry Association will handle cyberchondria in the upcoming DSM-5.

 

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Regorafenib, an Experimental Pill Tested in Colon and Rectal Cancer Patients, on Conference Agenda

Tomorrow the American Society of Clinical Oncology* will host its 9th annual GI Cancers Symposium. Bloomberg and the LA Times have already reported findings of a paper, still in abstract form, to be presented on Saturday.

The drug of interest is regorafenib, a pill that loosely inhibits quite a few kinases – enzymes critical in cell signals that control growth of normal cells, tumors and blood vessels. The experimental med, manufactured by Bayer, is also known as BAY 73-4506. The new data emerge from an international, randomized Phase III trial that goes by a loaded acronym: CORRECT.

The study included 760 patients with advanced colon or rectal cancer whose tumor progressed after receiving standard treatments. Participants received either the study drug or BSC (best supportive care) and a placebo. According to the paper, BSC includes antibiotics, pain meds, radiation for bone mets, steroids and some other treatments. The median survival in patients who received the Regorafenib was 6.4 months, compared with 5.0 months in patients who got the placebo. This difference, of 1.4 months in the median, was statistically significant. The “disease control rate” – a term that warrants separate explanation – was 44% in the regorafenib group c/w 15% in the placebo group.

The most frequent high-grade toxicities reported so far include a skin reaction affecting patients’ hands and feet, fatigue, diarrhea, elevated bilirubin in the blood, and high blood pressure. (Question to ask the oncologist who’s presenting these data at the meeting – was the elevated bilirubin from liver damage or hemolysis? With all the $millions spent on this trial, surely someone’s followed up on that detail.)

The language of the report and investigators’ comments are reminiscent of some regarding Avastin for advanced breast cancer. According to a media release: “…a subset of patients in the trial have responded particularly well to regorafenib, continuing to have stable disease for a relatively long time; research is ongoing to find ways to identify these individuals.” There are no biomarkers known to check for Regorafenib responsiveness.

What’s odd is that, according to the abstract, # LBA385, all patients entered the study between May, 2010 and March, 2011. This means some subjects were evaluated for less than a year, and the longest observation period for any patient on the trial is 20 months. Seems early to draw meaningful conclusions about the long-term toxicity and possible benefits of a cancer drug, especially for tumor types, like colorectal cancer, that don’t generally grow fast (c/w a condition like acute leukemia).

The list of investigators’ disclosures regarding ties to industry is too long to post here. You can find them at the tail end of the release. The FDA has assigned Fast Track status to this drug, according to Bayer.

*I am an ASCO member.

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ACS Issues Annual Report on Cancer Stats: Some Key Findings, and Notes on Survivorship

ACS (annual report header)

This week the ACS released its annual report on Cancer Facts and Figures in the U.S. The journal Cancer analyzes and considers the data in a helpful articleSome of the key and mainly positive findings have been covered elsewhere:

Between 1990 and 2008, death rates from cancer in the U.S. declined rather steadily, overall, by 22.9% in men and 15.3% in women. More recently, between 2004 and 2008, the incidence of cancer has declined slightly in men (0.6% per year) but it’s been stable in women. During this most recent period for which complete data are available, the overall death rates continued to drop – by 1.8% in men and by 1.6% per year in women.

This is generally good news. Still, the total number of people in the U.S. who will receive a new cancer diagnosis in 2012 is estimated at 1,638,910. Some 577,190 people will die of a malignancy, which approximates to 1,500 cancer deaths per day in the U.S. Cancer is second only to heart disease as the cause of death in North America. Most cancers, some 77%, arise in people aged 55 or older; conversely, approximately 23% arise in people under 55 years of age. The NIH estimates that in 2007, direct health expenditures for cancer in the U.S. totaled $103.8 billion.

Some notes on survivorship:

The latest estimate is that 12 million people are alive in the U.S. after a cancer diagnosis. This number includes people who are undergoing treatment and many who are in remission. Another encouraging detail: from 1975-77, the overall 5-year survival was just 49%. Now, between 2001 and 2007, overall 5-year survival stands at 67%. In other words, in 1975, just over half of cancer patients died within 5 years of their diagnosis; by 2007, two thirds of cancer patients were alive at 5 years.

The report includes a critical section on a few kinds of cancers for which the rates are increasing. These include cancer in the oropharynx (mouth and throat) associated with human papillomavirus (HPV); esophageal cancer (adenocarcinoma type), melanoma and tumors of the pancreas, liver, bile duct, thyroid, and some kinds of kidney cancer. The Cancer journal has a separate article on these.

The full and detailed document, at 68 printed pages, deserves close review in many particulars. Next week I’ll go over the new data for breast cancer.

All for now,

ES

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Blood and Hip Surgery: New Study Supports Fewer Transfusions

Under the radar, over the holiday week, the NEJM published a report on transfusion requirements in older adults who surgical hip repair. The main finding is that most patients, including the elderly and those at risk for cardiac complications of the procedure, don’t benefit from getting so many red blood cell transfusions as is commonly prescribed.

The study, funded by the NHLBI, involved more than 2000 adults over 50 years of age who underwent hip surgery. Overall the patients were quite elderly, with a mean age above 80 in each group. The trial included patients with heart disease and risk factors for cardiac complications. Participants were randomized to receive red blood cells if their hemoglobin fell to a level below one of either two thresholds: 10 or 8 gm/dl. What happened is that, at the time of discharge from the hospital and by 60 days after the procedure, the rates of death, coronary syndrome and other complications were the same.

An accompanying editorial weighs in on the study and conclusion, that a standard threshold for ordering transfusions in the context of major hip surgery might be lowered. Reducing transfusions would lower demands on the blood supply, lessen the costs of administering these infusions, and reduce complications from infected or otherwise-damaging pints.

The study is important because it bolsters the evidence that too many units of blood are administered routinely.  Sometimes with good reason, busy surgeons recommend a threshold for what’s almost an automatic order that blood to be given. If there is such a threshold in a SICU (surgical ICU), operating room or elsewhere, this report suggests it’s often too high.

It would be better, for sure, if transfusions were ordered on a case-by-case basis, with input by a doctor who would assess each patient’s baseline level of hemoglobin and other relevant factors. For example, a patient who’s been anemic for years may tolerate a lower hemoglobin level than someone who’s never been anemic before, or whose lung function is marginal.

Still, the main take is that many patients undergoing surgery need less blood than their doctors realize, and that we can safely, overall, reduce the number of transfusions ordered for many patients, even in those who are older and with risk of heart disease.

What patients might do: if you’re going to have major surgery, talk with your doctor about whether you might need blood and how the surgeon will decide if you need blood or not, and how much. If you have a strong preference to avoid transfusion, let your doctor know about that and discuss how you might avoid getting unnecessary pints.

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Noting the Death of Christopher Hitchens from Esophageal Cancer

The author is saddened to learn that Christopher Hitchens died late yesterday evening at the age of 62, roughly a year and a half after receiving a diagnosis of esophageal cancer. He was a prolific and articulate man; I respected him for his words.

His essays on the language and cancer might be of particular interest to some readers of this blog.

The NCI reports there are some 17,000 new cases of esophageal cancer in North American each year; it’s not a common tumor, and most cases arise in men. The annual number of deaths from esophageal cancer approaches 15,000 in the U.S. These numbers are telling: it’s not an easy disease to have, or to treat.

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Quote of the Day: On Death Panels and the Insurance Industry, From Dr. Donald Berwick

Dr. Donald Berwick left his position last week as head of CMS. He said this, as quoted in the WSJ’s Washington Wire, yesterday:

“Maybe a real death panel is a group of people who tell health care insurers that is it OK to take insurance away from people because they are sick or are at risk for becoming sick.”

I couldn’t agree with him more.

All for this week,

ES

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Learning From the San Antonio Breast Cancer Symposium, At a Distance

There’s a ton of BC and women’s health news this week. But yours truly is, among other things, not in San Antonio where is the 34th annual San Antonio Breast Cancer Symposium.

NTW, quite a few major news outlets are covering this business closely and carefully, as are some bloggers I know. Upon reading the news, I was simultaneously impressed by the number of new drugs for metastatic breast cancer that are being tried, and daunted upon realizing how difficult (read: IMPOSSIBLE) besides costly it’ll be to sort out these drugs used in so many combinations. Rather than recapitulating the data, some of which was published on-line this week in the NEJM, and most of which are still preliminary, I thought I’d just list some of the drugs being tested, and add a bit about how they’re administered and might work:

Entinostat is an oral histone deacetyalase (HDAC) inhibitor that’s not yet available in the US by any prescription off protocol.

Everolimus is a tablet (i.e. a pill) designed to inhibit an enzyme called mTOR. It’s sold for use in some cancers under the brand name Afinitor.

Exemestane is a tablet that reduces estrogen production. It’s an aromatase inhibitor sold as Aromasin. (This drug was approved by the FDA in 2005; it’s not quite so new, but is being tested in distinct settings, mainly in women with early-stage BC.)

Pertuzumab is a monoclonal antibody that binds Her2, in a distinct way from Herceptin.

Obviously this is but a partial list of drugs discussed at the meeting. Still, it’s heartening to this one oncologist to review even a short list of diverse new agents that might arrest the disease.

The history of the SABCS is interesting.  From the organization’s website:  the first meeting was held in November 11, 1978 during what’s said to have been “Breast Cancer Awareness Week.” The original conference’s sponsors included the Cancer Therapy and Research Center (CTRC, at UT San Antonio), the Texas Division of the ACS, the University of Texas Health Science Center at San Antonio (UTHSCSA) and the Bexar County Medical Society. Some 141 physicians and surgeons attended what’s described as one-day course.

It grew…

Now, the SABCS hosts a 5-day program with physicians, scientists, patients, advocates, reporters…from around the world. It’s jointly-sponsored by the CTRC and American Association for Cancer Research (AACR) and the Baylor College of Medicine.

The Alamo (WC image)

Next year, maybe I’ll go to the 35th annual event, and see what’s really happening in San Antonio.

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Final Word on Avastin, and Why We Need Better Physicians

Today’s breaking breast cancer news is on Avastin. The FDA has just announced, formally, that it will rescind approval for the drug’s use in people with metastatic breast cancer. Commissioner Dr. Margaret Hamburg writes this her statement:

I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients, and those who support them, to ask hard questions and demand explanations concerning the drugs that are recommended to treat serious illnesses.

On this much I agree with Dr. Hamburg – that patients and others, including doctors who prescribe treatments to patients with likely incurable illnesses, and all medical conditions, for that matter, should ask hard questions.

Others have already, immediately expressed that the FDA did the right thing. Because they think the FDA’s decision was rational, and it was. Likely there’ll be an editorial in the paper I usually read, celebrating the victory of reason over anecdote. The WSJ, whose words tend to align more with business interests, will likely be critical. Opponents of health care reform will, inappropriately and mistakenly, use this as an example of rationing, which it isn’t.

The fact is that many, and possibly most, medical treatments are given in the absence of studies to justify their use. So you might ask, instead, why give chemotherapy to most stage IV cancer patients. Or why give it in the adjuvant setting? Apart from some tumors, like some kinds of lymphoma and leukemia, and common breast and testicular cancers, and a few others, when carefully measured the benefit is often slim.

What I think is that Avastin is a scapegoat of sorts, a costly drug not particularly worse than many others, nor better, and that helps a small minority of women with a lethal disease for reasons their doctors can’t predict or explain.

We experiment, on insurance and Medicare dollars, with so many costly treatments. Bone marrow transplants, at a cost of hundreds of thousands of dollars per patient, for example, are given to some with little formal proof of benefit for the approved indications. But there’s a lobby for these treatments. Support comes from hospitals profiting from transplant procedures and, more subtly, from academic physicians who’ve built careers in that field and write papers about their benefits, complications and management. I might cite other complex, costly and unproved examples in oncology, surgery and other fields of medicine, but that’s not the real point for today.

What I wonder is, ironically, because the data on Avastin were collected so carefully, that its lack of effectiveness over a population of women was better-documented than has been the lack of evidence for other drugs and regimens. Besides, there’s no group of hospitals and doctors whose profit and livelihood, respectively, depends on giving Avastin to just a few people with metastatic breast cancer. There was just Genentech, an easy big-Pharma target, and a few women, pleading for continued access to a drug that’s helped to keep them alive.

(I wonder, also, had those patients who testified been men, would their words have been taken more seriously?)

Meanwhile, doctors can keep giving Avastin to patients with other forms of cancer, for which its efficacy is not so different as you might think. Like any drug, this drug’s response varies from patient to patient for every tumor type that it might be given. And the physicians can still give Avastin, as the commissioner points out in her decision, to women who can pay for it, by circumstances of their particular insurance, or good fortune of wealth. But some of these women’s families will be hurt hard by this FDA decision. Most are in the 99%.

And so maybe what we really need are better doctors, not only in oncology, who would carefully monitor patients when they give any and every medical treatment and stop it if it’s not working, and continue only if it helps, and would communicate and obtain informed consent through meaningful discourse.

If we had that, we’d save a lot of money, and get better care.

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iPod Therapy – Why Not Prescribe It?

Yours truly, the author of Medical Lessons, is listening to music while she writes. A live version of the Stones’ “Silver Train” has just come on, and she’s happily reminded of something that happened 30 years ago. Distracting? Yes. Calming? Yes. Paradoxically helps to keep me on track? Yes.

My iPod keeps my mind from wandering further. And it lifts my mood.

And so here, on my blog, which is not peer-reviewed or anything like that, I put forth the medical concept of “iPod therapy.”

“When you’re weary, feeling small…” Music can help.

Today’s news reports that 1 in 5 Americans take drugs for psychiatric conditions. That sounds like a lot to me, but I’m no pharmaceutical surveyor. Of course many people need and benefit from medical help for depression and other mental illnesses.

But, in all seriousness, I wonder how many people might use music like a drug to keep them relaxed, happy, alert…

Why not prescribe music? It works for me, n=1.

Maybe doctors should be recommending iPods, or radios, or Pandora to some of their patients who are feeling down. I hope an academic psychiatrist somewhere, without ties to Apple or Pandora or Bose or other relevant party is coordinating a careful, prospective study of this promising and relatively inexpensive intervention.

As best I can tell, music is non-addictive. Except that if I had to live without it, I’d start humming, or maybe singing, which might be detrimental to those who live near.

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Magic Johnson is Alive 20 Years after Announcing He Had HIV

Yesterday’s Washington Post Sports has a clip from CNN, 20 years ago, when basketball star Magic Johnson announced on TV that he had HIV, the virus that causes AIDS. The date was Nov 7, 1991.

“Where were you when Magic made his announcement? What were your thoughts on Johnson and HIV/AIDS that day and how have they changed?” asks Matt Brooks in his column.

I can’t quite recall where I was. Probably I was at the hospital working, possibly even taking care of a patient with HIV. But I do remember thinking how much courage it must have taken for him to come out with it.

He understood, likely, that he would die soon, and his doctors probably thought the same. There were only two antiviral drugs approved for HIV back then. There was so much stigma, and fear.

Today you can see and listen to him in an interview on ESPN.

It’s great to see Magic Johnson back in the news, even if it’s (just) in a sports sections, and to be reminded that he’s alive, doing OK. The condition we thought was a death sentence has become a chronic illness, with so many drugs available for treatment it’s hard to keep track.

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On Alcohol and Breast Cancer, Guilt, Correlations, Fun, Moderation, Doctors’ Habits, Advice and Herbal Tea

Few BC news items irk some women I know more than those linking alcohol consumption to the Disease. Joy-draining results like those reported this week serve up a double-whammy of guilt: first – that you might have developed cancer because you drank a bit, or a lot, or however much defines more than you should have imbibed; and second – now that you’ve had BC, the results dictate, or suggest at least, it’s best not to drink alcohol.

The problem is this: If you’ve had BC and might enjoy a glass of wine, or a margarita or two at a party, or a glass of whiskey, straight, at a bar, or after work with colleagues, or when you’re alone with your cat, for example, you might end up feeling really bad about it – worse than if you had only to worry about the usual stuff like liver disease and brain damage, or if you could simply experience pleasure like others, as they choose.

The newly-published correlative data, in the Nov 2 issue of JAMA, are clear. The findings, an offshoot of the Nurses’ Health Study, involve over 105,000 women monitored from 1980 until 2008. The bottom line is that even low levels of alcohol consumption, the equivalent to 3-6 drinks per week, are associated with a statistically significant but slight increase in breast cancer incidence. And the more a woman drinks, the more likely she is to develop breast cancer.

All things considered, it might be true that alcohol is a breast carcinogen, as Dr. Steven Narod calls it in the editorial accompanying the research study. Still, there’s no proof of cause and effect: Other factors, like consuming lots of food or perhaps some yet-unidentified particularity about living in communities with abundant food and alcohol, are potential co-variables in this story. But what if it is true?

From the editorial:

These findings raise an important clinical question: should postmenopausal women stop drinking to reduce their risk of breast cancer? For some women the increase in risk of breast cancer may be considered substantial enough that cessation would seem prudent. However, there are no data to provide assurance that giving up alcohol will reduce breast cancer risk.

How I see it is this: Everything’s best in moderation, including enjoyment of one’s life. You work, you rest, you have some fun.

This evidence is not like the strong data linking cigarettes to smoking that officials sat on for a few decades under the influence of the tobacco industry. This is a plausible, mild, and at this point well-documented correlation.

I don’t deny the sometimes harmful effects of alcohol; no sane physician or educated person could. But if you have a glass of wine, or even a second, so long as you don’t drive a car or work while affected, I don’t see it as anyone’s business but your own. More generally, I worry about how much judging there is by people who behave imperfectly, and how that can make individuals who are good people in most ways feel like they don’t deserve to be happy or enjoy their lives.

Women, in my experience, are generally more vulnerable to the put-downs of others. And so my concern about the BC-alcohol link is that this will, somehow, be used, or have the effect of, making survivors or thrivers or women who haven’t even had breast cancer feel like they’re doing the wrong thing if they go to a party and have a drink. And then they’ll feel badly about themselves.

Really I’m not sure what more to say on this loaded topic, except that it points to the deeper and broader ethical dilemma of doctors who are not all perfect examples of moderation, expecting and asking other people to change their personal habits when they themselves like to go out and have fun, and drink, at parties, or have wine in the evenings over dinner in the privacy of their homes.

How shall I resolve this post?

Last night I sipped Sleepytime tea, manufactured by Celestial Seasonings, before reading a book. The stuff is said to be 100% natural, with “a soothing blend of chamomile, spearmint and lemongrass.” I tried it first a few weeks ago and, by a placebo effect or through real chemistry, it helps me sleep more soundly.

I’ve absolutely no idea what are the effects of “Sleepytime tea” on breast cancer. It might help, it might hurt, or it might do nothing at all.

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Mammograms Could Save More Lives Than You Might Think

I’m wondering is how to bring mainstream health journalists and women who are, lately, choosing not to have mammograms, to their senses about a persuasive but flawed argument put forth by a Dartmouth epidemiologist and others in a crew of seemingly like-minded, hopefully well-intentioned, some perhaps tenure-seeking and others grant-needing, circulatory bias-confirming academics who meet and discuss and write about the so-called dangers of mammography.

Maybe some doctors and journalists think they’re doing the right thing by informing a naïve body of women who, in the words of an LA Times writer today, think only correlative and simple thoughts.

From Screening mammograms save fewer lives than you think:

If you or someone you know discovered she had breast cancer thanks to routine mammography screening, and if you or that friend with breast cancer got treatment and today is cancer-free, it’s natural to assume that the mammogram was a life-saver.

But odds are, it wasn’t….

First things first: the title makes an assumption about what I, or you, or any reader, thinks.

Second, the story offers two factoids: first – that over 75% of women diagnosed with BC by screening mammography wouldn’t have died from the cancer if they hadn’t had mammography; and second – that no more than 25% of those same women can rightly credit a mammogram for saving their lives. But this is just one stat, or falsehood, based on the true, assumption-free relationship between 75% and 25%.

Dr. H. Gilbert Welch, who recently likened mammography-taking to gambling, plays freely with impressive-sounding information sources. He and his coauthor used data from the NCI. Seemingly hard to argue with those kinds of numbers. But they used old data, again, and employ numerous assumptions (what the authors call generous, but I wouldn’t) to render calculations and “prove” their point published in the Archives of Internal Medicine.

The manipulative tone is set in the paper’s abstract:

“…We created a simple method to estimate the probability that a woman with screen-detected breast cancer has had her life saved…

Simple? Don’t you believe it.

There’s a Well post in the New York Times today covering the same Archives of Internal Medicine article. Not surprisingly, this draws positive feedback in the comments and Twitter-chatter. Some of the more understandable discussion comes from women with metastatic disease whose tumors were missed by screening mammography. Notably, neither paper quotes an oncologist.

Here in the U.S. where we do spend too much on health care, we all know women whose breast tumors were missed by screening mammograms. This happens, and it’s awful, but it doesn’t and certainly shouldn’t happen so often as some doctors seem to think. Extrapolating from personal observations to draw conclusions about a procedure’s value is flawed reasoning, either way.

I agree with many of Dr. Susan Love’s school, and most of the NBCC agenda, and others that say breast cancer prevention would be better than treatment. How could I not?

But until there’s a prevention for BC, which I’m sorry to report is unlikely to happen before 2020, especially because it’s really 15 or 20 or maybe even more diseases that would, presumably, need distinct methods of prevention, and until there are better, less damaging and less costly remedies, mammography may be the best way for middle-aged women to avoid the debilitating and lethal effects of late-stage disease. And for society to avoid the costs of that condition and its treatments, which are huge.

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post shortened 12/18/12

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