Vicious Verbiage Targets Cancer Patients’ Voices, at Cardiobrief

A journalist who covers medical matters of the heart grabbed my attention on the Fourth of July. In The Voice of the Patient: Time To Bring Out the Muzzle?, Larry Husten at Forbes’ Cardiobrief blog, insinuates that the women who spoke at the FDA’s Avastin hearings are simpletons.

In his short strip, Husten skips the possibility that the testifying patients might understand science. He dismisses their familiarity with Avastin. He ignores their potential informational value as bona fide outliers, and jumps to this killer conclusion:

…When reporters cater to these type of people they not only foster fuzzy thinking, they encourage a mob mentality that tears down any semblance of rationality or any possibility of intelligent discourse.

Medicine, of course, is all about the patient. But that doesn’t mean that every patient is right, or deserves a public voice, or that uncritical journalists should assist them in metastasizing their views.

This is rare language in a business journal:

Phrases like “these type of people” and “mob mentality” typically reflect fear of others, based in prejudice – the opposite of reason and science, to which the author aspires. Likening patients speaking out to “metastasizing,” a term normally applied to the lethal movement of cancerous cells, reveals a disturbed view of people with illness.

The Forbes Headline, in which the author and editor, or both, contemplate using a “muzzle” to silence patients, does not approach the norm in health care journalism, or even opinion-writing.

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No Room For Emotion or Exceptions to the Rule (on Avastin)

My cousin testified before the FDA oncology advisory board on Tuesday about her experience taking Avastin. This is a tragedy, to deny the only drug that is keeping a 51 year old woman alive.

image from p.3 of today’s NYTimes business section

You have to wonder, are the advisory panel members so rational in all their behavior and choices? Are they always so razor-like in their oncology decisions?

Unlikely.

These experts have an agenda, here: It’s to be perceived as scientists, even when their knowledge is imperfect and exceptions to the rule stand right in front of their eyes. But clinical medicine calls for flexibility, and tailoring of treatment to each case, and caring about each person, including those who fall at the tail, or in this case better end, of any Kaplan-Meier survival curve.

What would Larry Kramer do about this, I’ve been thinking: He’d scream, really loud, so loud he might break his eardrums. He’d wonder why others, affected and near, aren’t doing the same. And he’d understand why this picture is on page 3 of the business section, and not on the front cover; it’s because people don’t want to look or see or know or think about it too much, because it hurts.

That is the normal heart, and this is a normal response to what’s happening to women with metastatic breast cancer.

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FDA Approves New Assay for Her2 in Breast Cancer

This week the FDA approved a new assay for Her2 expression in breast cancer biopsies. The technology, Inform Dual ISH, is manufactured by Ventana Medical Systems, a Roche subsidiary.

From Ventana Medical: the HER2 and Chromosome 17 probes are detected using two color chromogenic in situ hybridization (ISH)

Inform Dual ISH works like this: technicians, typically working under the supervision of a pathologist, expose a tiny bit of a breast biopsy specimen, fixed on a microscope slide, to probes for Her2. This gene, normally found on human chromosome 17, is amplified in some breast cancer cells. The assay exploits an enzyme, linked to the genetic probe, which creates a color (in this case, red) upon exposure to a chemical. The system allows a pathologist, using a microscope, to “see” and measure the gene’s presence on chromosomes in cells of an ordinary biopsy sample.

What’s interesting about this in situ hybridization (ISH) kit is that it doesn’t require a fluorescent microscope for imaging. The Ventana probe generates a simpler, ordinary color signal that can be detected by a light microscope. Most commercial assays for Her2 use a method called immunohistochemistry (IHC); that technique relies on antibodies that bind Her2, a cell surface receptor that’s implicated in cancer cell signaling and growth. This and other ISH assays measure genes directly on the chromosomes; by contrast, IHC usually tests for protein.

Her2 is the molecular target for Herceptin, and there’s been considered discussion about how and where it might be accurately assessed. So the “readout” from this diagnostic test might inform a woman and her doctor in deciding whether or not she should receive treatment with Herceptin.

How pathologists evaluate breast biopsy specimens matters a lot, especially when you’re on the receiving end of a diagnosis and you’re choosing among treatments. In 2007, ASCO and the College of American Pathologists published guidelines on Her2 testing in the Journal of Clinical Oncology. These groups recently updated the recommendations. How this new assay will be received by these societies, I’m not sure.

A key question, in this author’s mind, is where the Her2 measurements take place, and whether women should rely on local labs’ assays – by whatever method – to determine the Her2-ness of their breast tumors.

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Considering Aromasin for Healthy Women, and the New Breast Cancer Prevention Study

I’m minding the annual meeting of the American Society of Clinical Oncology from a distance this year.

So far, the big breast cancer story syncs with a NEJM paper published yesterday on-line, on the use of exemestane (brand name: Aromasin, manufactured by Pfizer) to prevent invasive breast cancer. These patent-protected pills block the body’s normal production of estrogen.

The main finding was that for women deemed “at risk” for developing BC – as defined by the investigators – the incidence of cancer was significantly reduced when they took Aromasin as compared to a placebo. At a median observation point of 35 months, there was no observed effect on the women’s survival.

What’s right about the study: it’s prospective, randomized and large, including over 4560 women. The results are clear in terms of percents and relative risks: There was a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%) and a hazard ratio of 0.35 (with confidence interval 0.18 to 0.70; P=0.002). So they’ve got strong stats.

Estrogen, typically depleted but not absent in post-menopausal women, can promote growth of breast cancer cells. From the paper’s first section: “Aromatase inhibitors profoundly suppress estrogen levels in postmenopausal women and inhibit the development of breast cancer in laboratory models.” So the findings are plausible, which helps, too.

The first problem (or non-problem, really) is there were only 43 cases of invasive BC in total; there wasn’t much cancer, or its reduction, in either arm of the study in terms of absolute numbers. This makes the divergent percents reported seem far less impressive. Second, and more importantly – the long-term consequences of taking this relatively new estrogen-inhibiting drug, in terms of women having thinner bones, possibly more cardiovascular disease, diminished libido and other side effects, are unknown.

Already there are two drugs marketed to prevent breast cancer in some women: tamoxifen and raloxifene. These drugs, also anti-estrogens, have significant side effects including blood clots, and few women choose to take them as prophylaxis for breast cancer. The new study suggests Aromasin is better because it’s got fewer side effects; Pfizer’s idea is that it’s a safer option for women who want to reduce their risk of developing BC.

But what caught my attention is who qualified for this trial: Most healthy women over the age of 60 – that’s a whopping, growing population of potential Aromasin-takers, besides the relatively small number of women with known pathology such as precancerous or stage 0 breast cancer (conditions like LCIS and DCIS, for which a preventive drug seems justifiable) or high risk-conferring BRCA-1 or -2 mutations.

Reading over the trial’s eligibility, I had to wonder, how could anyone think it reasonable to treat all women over the age of 60 with an estrogen inhibitor? And who populated the IRBs that approved this protocol? (Imagine if oncologists were to propose testing the effects of chemical castration in thousands of men over the age of 60; few would support such a trial, although in all likelihood androgen ablation would reduce the incidence of prostate cancer in men.)

The NEJM article lists support for the work from the Canadian Cancer Society Research Institute, the Canadian Institutes for Health Research, Pfizer, and the Avon Foundation. Among my many questions, I’d like to know what exactly what fraction of the study’s support came from Pfizer. The Journal (and every) should break this down for a published non-advertisement: If Pfizer provided 5% or 50% or 95% of funding for the trial, readers should be informed, as should women who might choose to take this drug and their doctors who might prescribe it.

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Get Off My Case

In my inbox this morning, via ASCO‘s “Cancer in the News” feed:

The UK’s Telegraph (5/6, Beckford) reported that as “many as 20,000 British women could avoid developing” breast cancer “each year, if they took more exercise, drank less and ate better.” Latest figures “suggest that 47,600 women developed breast cancer in 2008,” and the World Cancer Research Fund estimates that estimates that “42 per cent of these cases…would be preventable if women developed healthier lifestyles.” The WCRF’s “10 Recommendations for Cancer Prevention include being ‘as lean as possible without becoming underweight’; keeping fit; limiting consumption of fatty, salty and sugary food and drink; eating fruit, vegetables and pulses; eating less red meat and processed meat; drinking less and choosing a balanced diet rather than vitamin supplements.”

This follows numerous reports that women may develop breast cancer or suffer recurrences because they eat too much, drink too much, work too much or fret too much. (But don’t relax and put down your vacuums, girls – there’s striking evidence that household chores can reduce your risk!)

Of course it’s wise from a general medical perspective – think in terms of heart disease, osteoarthritis, type 2 diabetes and other ailments prevalent in our too-developed world – to be slender instead of fat, exercise regularly and eat a balanced diet.

I’m tired of the press trumpeting poorly-done trials that feed into a stereotypic conception of how women should behave. Yes, diet and stress could play a role in any hormone-driven disease, but so do a lot of things. As for alcohol, maybe consumption is a surrogate for wealth and living in a place like the U.S. where people drink freely, where breast cancer rates are unseemly.

We should be sure of the facts before pronouncing these fatal flaws in our ways of existence and being. Plenty of women feel badly about their tumors and disfigurement without this added layer of insult.

And what did you eat for dinner last night, big brother?

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New York City Reports Long Delays for Mammograms

A recent audit of nine NYC’s Health and Hospitals Corporation found City Comptroller Liu described as dangerous delays in women’s health care. It takes too long for women to get screening and diagnostic mammograms.

The 2009 audit found women at Elmhurst Hospital had the longest waits – 50 working days (that would be 10 weeks, i.e. 2.5 months) for diagnostic mammograms, on average. You can find more details here.

According to the Times’ coverage:

Ana Marengo, a spokeswoman for the city’s Health and Hospitals Corporation, which runs the public health system, said that the comptroller’s data was outdated…

At Elmhurst, she said, the wait as of December 2010 was 20 days for screening and 23 days for a general diagnostic test, as opposed to an urgent one.

Still, at Queens Hospital Center, the wait for a screening test was 56 days in December <2010>, Ms. Marengo said. “It’s due to volume and higher demand,” she said. “We only have a certain amount of resources.”

From the comptroller’s press release, a statement from Alice Yaker, Executive Director, of SHARE: Self-help for Women with Breast or Ovarian Cancer:

“While controversies about efficacy surround the screening of healthy women, there is no controversy about the need for a diagnostic mammogram in a woman who presents with a lump in her breast, for example. This requires our urgent attention, budget cuts and hospital closings notwithstanding.”

The comptroller’s message says there’s no guideline for how soon a woman with breast cancer symptoms, such as a lump, should receive a diagnostic mammogram. For screening, guidelines suggest the wait be no longer than 14 days for an appointment.

This blogger’s vote: set up a maximum wait time for diagnostic mammography: 10 working days.

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New Study, Presented at a Meeting of Breast Surgeons, Supports that Mammograms Save Lives of Women in Their 40s

The American Society of Breast Surgeons held its 2011 annual meeting in D.C. from April 27 – May 1. Among the papers presented was Abstract #1754: “Mammography in 40 Year Old Women: The Potential Impact of the U.S. Preventative Services Task Force (USPSTF) Mammography Guidelines.” You can find the press release, followed by the abstract, here. The main result was that screening women ages 40-49 by mammography was associated with finding smaller tumors, with less spread to the lymph nodes, than clinical breast exams alone, and this correlates with improved survival at 5 years.

The study, put forth by a group at the University of Missouri-Columbia in Columbia, MO, is  based on a 10-year retrospective chart review, from 1998 – 2008, of 1581 women treated for breast cancer at that institution. In this author’s opinion, a retrospective, chart-review type analysis of a medical intervention is about as low as you can get on the quality-of-data scale in a medical study. And, as emphasized by Dr. Otis Brawley, chief medical officer of the ACS as quoted in HeathDay’s report on the matter, these are tentative findings, presented in abstract form at a meeting. He suggested that the 5-year follow-up is too short.

That said, I think the findings are significant and likely reflect what happens when mammography screening is done right, which is that it saves lives in women 40 and older.

The results focused on the 320 women – 20% of all those treated for breast cancer at the institution – between the ages of 40 and 49 at the time of breast cancer diagnosis. Among those, mammography detected the tumors in just under half (47%) of the cases; in 53%, there was a palpable mass – the “clinical detection” group. In those with cancers were detected by mammography, the average tumor size was 2 cm in diameter; in the clinical detection group, the average size was 3 cm. (From an oncologist’s perspective that’s a huge difference; for most breast cancer subtypes that 1 cm difference in diameter portends a distinct prognosis.) What’s more, the frequency of lymph node involvement in the clinical detection group was 56%, more than twice that in the mammography group (25%), another prognosis-changer. These findings were highly significant from a statistical perspective, with p-values <0.0001.

The researchers confirmed that negative lymph nodes and smaller tumors were associated with longer survival. They estimated that disease-free survival, at five years, was 94 percent for women under 50 who received mammograms and 78 percent for those who did not receive the screening exams. Five year overall survival rates for each group were 97% and 78%, respectively.

These figures have huge implications, especially if you multiply the potential survival benefit – on the order of 20 percent at 5 years, or greater, depending on how you look at it – across over some 21.5 million women in the U.S. between the ages of 40 and 50, approximately 1.5 in 1000 of whom will be found to have invasive BC per year.*

Reuters ran this story on April 29  as did HealthDay. Both ran quotes by Dr. Paul Dale, chief of surgical oncology at the University of Missouri School of Medicine and lead author of the abstract. The findings suggest that adherence to the updated U.S. Preventive Service Task Force (USPSTF) guidelines, which do not recommend screening mammography for most women between the ages of 40 and 49, would lead to preventable deaths.

One thing the author of ML learned this morning is that Dr. Virginia Moyer, the new chair of the USPSTF and who is quoted in the HealthDay coverage, is a pediatrician and professor with a public health degree.

*based on U.S. Census data of 2000 and SEER data incidence (BC, all races, by age) accessed 5/2/11

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The Trouble With Ginger

A short post for Friday:

The Times published a short piece on ginger this Tuesday, on whether or not it relieves morning sickness. The conclusion is that it’s less effective for nausea in pregnancy than in seasickness and chemotherapy treatment.

When I was getting chemo, I received a gift of ginger tea. It didn’t help at all. Now, if I even sniff that stuff, I want to throw up.

Curiously, I have no problems with ginger in food. I use the fresh ingredient all the time.

No explanation –

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About the Premarin Study and Breast Cancer

This week a paper came out in JAMA showing a surprising reduction in breast cancer cases among women who had hysterectomies and then took Premarin, an estrogen-only remedy compounded from steroids in horses’ urine.

drawing of a horse (Wiki-Commons)

The research merits attention because it’s part of the Women’s Health Initiative and is well-done by several measures: The study is large, placebo-controlled and randomized. The investigators followed 10,739 post-menopausal women ages 50-79, all who previously had surgical removal of the uterus. The women took CEE (conjugated equine estrogens) at a dose of 0.625 mg by mouth per day, or a placebo. The trial was stopped a year early, after an average follow-up of seven years, after the analysts noted that more women taking Premarin had strokes. But I digress…

The main findings were two: 1) Premarin, at the dose prescribed, had no clear effect on cardiovascular disease, overall, either way; and 2) there was a significant reduction in invasive breast cancer among women taking estrogen in this study. More precisely: the incidence of BC was 0.27% in women who took Premarin and 0.35% in the placebo group. For the stats-guys: the relative risk (RR) was 0.77, with 95% confidence intervals of 0.62-0.95.

The findings were covered by major news organizations and other women’s health bloggers. Still you may wonder, what’s ML’s take on this subject?

According to the Times as many as a third of women in the U.S. have had hysterectomies. The CDC says that approximately 600,000 hysterectomies are performed each year in the U.S. No matter what the numbers – which seem to me discordant – my first reaction is to wonder why so many women have their uterus removed.

About the apparently lower incidence of breast cancer, it may be that this particular dose of estrogen in the form of Premarin does tend to reduce or somehow suppress BC in post-menopausal women who’ve had hysterectomies.

But it could just as well be a statistical fluke-

If you examine a sufficient number of outcomes in a research group of thousands of women, you’re likely to find one aberration or another. What we do know is that most breast cancer cells do express receptors for estrogen, which can stimulate those cells’ growth.

Presumably, time and the scientific process will yield the truth about Premarin and other hormones some people take so that they might feel better. Then again

Personally, I wouldn’t go near the stuff.

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On My Mind

Yesterday I checked in on the Cancer Culture Chronicles, a thoughtful and sometimes funny blog by Anna Rachnel, who lives with metastatic breast cancer.

There I learned that the author of Living With Cancer, a blog I’d read occasionally and has been in the back of my mind lately, is dead. Sadly, I never had the chance to meet or speak with Daria.

From a eulogy in the final blog entry: She was born in 1961 in Alberta, Canada. Her breast cancer diagnosis came on in 2000, when she was 39 years old. She received surgery, chemo and radiation and additional meds. According to her first blog entry of August 2008, she’d had a local recurrence in 2004. The disease came back on the other side and elsewhere around then she started her blog. Among other things she accomplished in her life, about which I know too little, she participated in a clinical trial of an experimental drug, Brivanib, and advocated for cancer patients by speaking with members of the Canadian Parliament. She died this past January, a few days before her 50th birthday, survived by her mother, sisters, brother and husband.

From Daria’s first post, upon her 2008 recurrence: “…It is still too difficult to discuss the details. I’m hoping that sharing my experience will help me cope with the reality of my illness.”

Based on what’s evident on the blog, it seems likely that the on-line writing probably did help her, personally and individually. But perhaps, even more so, the blog is instructive for others, now. I suspect there’s a lot more I and others might learn from her story and digital afterlife.

With respect

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New Data for Avastin (Bevacizumab)

A new report was published on-line this afternoon by the Journal of Clinical Oncology (JCO). It covers a Phase III (randomized) clinical trial of Avastin (Bevacizumab) in women with metastatic BC. Over 1200 patients were included in the analysis, all with Her2 negative disease.

The design of the randomized study protocol was a bit unusual, in that the treating physicians could choose among a few, standard chemo options to give their patients – the so-called “backbone” for treatment for each cohort in the trial, along with hormonal treatment and the study drug: Avastin or a placebo. Avastin is a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF). It’s manufactured by Roche and is quite costly.

What the investigators report, now, is that women who received Avastin and any of the chemo regimens did better – in terms of what’s called progression free survival – than did those who received the same chemo and placebo treatment. The difference was a matter of a few months, on average, and there were no measurable change in overall survival. What this means is that in some women with metastatic breast cancer, Avastin appears to help keep the disease in check.

The study is called RIBBON-1, which I learned this evening would be for the first study of Regimens in Bevacizumab for Breast Oncology. Sounds lame, I know, but believe me – it’s hard for oncologists to keep trials straight without acronyms. Even with the acronyms.

It happens I know some women with triple negative BC who have benefited from Avastin. These women may be outliers on the curve, but they are real and they exist and I know them personally, in what should be the middle of their lives.

Maybe we, and the FDA, shouldn’t give up so fast on Avastin.

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Breast Cancer Rate in the U.S. is No Longer Declining

A worrisome report on breast cancer trends in the U.S. appeared on-line today, ahead of print in an AACR journal, Cancer Epidemiology, Biomarkers & Prevention.

The analysis, based on the NCI’s SEER data from 2000 – 2007, shows that the incidence of breast cancer in the U.S. is no longer declining. (A drop after 2002 in BC incidence is generally attributed to an abrupt reduction in HRT around that time.)

Since 2003 the overall BC rate has been steady overall, with a few exceptions:

The incidence of BC in non-Hispanic white women ages 60-69 rose by 4.8% in this period. “It remains to be seen if this trend will continue,” according to the study authors.

Among white women ages 40-49 rates of estrogen receptor (ER) positive (ER+) breast cancer significantly increased by an average of 2.7% per year during this period. In contrast, the rate of ER- breast tumors decreased, overall, although the trends were statistically significant only for women ages 40-49 and 60-69.

Apart from women younger than 40, overall BC rates and ER+ case rates were highest among non-Hispanic white women, followed by non-Hispanic black and Hispanic women. Among black women ages 40-49, the incidence of ER+ BC increased (5.2% per year) during 2003-2007, and there were non-significant, recent increases in ER+ BC among older black women.

Of note, in contrast to the pattern for ER+ breast cancer, non-Hispanic black women have the highest rates of ER- breast cancer in every age group. (These ER- cases would include triple negative BC.)

Sorry for the jargon, readers – I hadn’t planned to post now. But I think this information warrants attention.

This matters for a number of reasons. First, it’s bad news in terms of women’s health, plain and simple. Second, these numbers relate to the mammography math, which has been on my mind lately. The point is that if more women between the ages of 40 and 49 are developing ER+ (read: most treatable) tumors, this would influence the net benefit of cancer screening in that age group.

And please don’t misread me here: This is not an academic argument I want to win. Rather, I wish the incidence of breast cancer were declining. And I wish, even more, that so many middle-aged women I know personally weren’t affected by this devastating illness.

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Radiologists’ Experience Matters in Mammography Outcomes

There’s a new study out on mammography with important implications for breast cancer screening. The main result is that when radiologists review more mammograms per year, the rate of false positives declines.

The stated purpose of the research,* published in the journal Radiology, was to see how radiologists’ interpretive volume – essentially the number of mammograms read per year – affects their performance in breast cancer screening.  The investigators collected data from six registries participating in the NCI’s Breast Cancer Surveillance Consortium, involving 120 radiologists who interpreted 783,965 screening mammograms from 2002 to 2006. So it was a big study, at least in terms of the number of images and outcomes assessed.

First – and before reaching any conclusions – the variance among seasoned radiologists’ everyday experience reading mammograms is striking. From the paper:

…We studied 120 radiologists with a median age of 54 years (range, 37–74 years); most worked full time (75%), had 20 or more years of experience (53%), and had no fellowship training in breast imaging (92%). Time spent in breast imaging varied, with 26% of radiologists working less than 20% and 33% working 80%–100% of their time in breast imaging. Most (61%) interpreted 1000–2999 mammograms annually, with 9% interpreting 5000 or more mammograms.

So they’re looking at a diverse bunch of radiologists reading mammograms, as young as 37 and as old as 74, most with no extra training in the subspecialty. The fraction of work effort spent on breast imaging –presumably mammography, sonos and MRIs – ranged from a quarter of the group (26%) who spend less than a fifth of their time on it and a third (33%) who spend almost all of their time on breast imaging studies.

The investigators summarize their findings in the abstract:

The mean false-positive rate was 9.1% (95% CI: 8.1%, 10.1%), with rates significantly higher for radiologists who had the lowest total (P = .008) and screening (P = .015) volumes. Radiologists with low diagnostic volume (P = .004 and P = .008) and a greater screening focus (P = .003 and P = .002) had significantly lower false-positive and cancer detection rates, respectively. Median invasive tumor size and proportion of cancers detected at early stages did not vary by volume.

This means is that radiologists who review more mammograms are better at reading them correctly. The main difference is that they are less likely to call a false positive. Their work is otherwise comparable, mainly in terms of cancers identified.**

Why this matters is because the costs of false positives – emotional (which I have argued shouldn’t matter so much), physical (surgery, complications of surgery, scars) and financial (costs of biopsies and surgery) are said to be the main problem with breast cancer screening by mammography. If we can reduce the false positive rate, BC screening becomes more efficient and safer.

Time provides the only major press coverage I found on this study, and suggests the findings may be counter-intuitive. I guess the notion is that radiologists might tire of reading so many films, or that a higher volume of work is inherently detrimental.

But I wasn’t at all surprised, nor do I find the results counter-intuitive: the more time a medical specialist spends doing the same sort of work – say examining blood cells under the microscope, as I used to do, routinely – the more likely that doctor will know the difference between a benign variant and a likely sign of malignancy.

Finally, the authors point to the potential problem of inaccessibility of specialized radiologists – an argument against greater requirements, in terms of the number of mammograms a radiologist needs to read per year to be deemed qualified by the FDA and MQSA. The point is that in some rural areas, women wouldn’t have access to mammography if there’s more stringency on radiologists’ volume. But I don’t see this accessibility problem as a valid issue. If the images were all digital, the doctor’s location shouldn’t matter at all.

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*The work, put forth by the Group Health Research Institute and involving a broad range or investigators including biostatisticians, public health specialists, radiologists from institutions across the U.S., received significant funding from the ACS,  the Longaberger Company’s Horizon of Hope Campaign, the Breast Cancer Stamp Fund, the Agency for Healthcare Research and Quality (AHRQ) and the NCI.

**I recommend a read of the full paper and in particular the discussion section, if you can access it through a library or elsewhere. It’s fairly long, and includes some nuanced findings I could not fully cover here.

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New Numbers Should Factor Into the Mammography Equation

On Friday the New York Times reported that surgeons are performing far too many open breast biopsies to evaluate abnormal mammogram results. A new American Journal of Surgery article analyzed data for 172,342 outpatient breast biopsies in the state of Florida. The main finding is that between 2003 and 2008, surgeons performed open biopsies in an operating room – as opposed to less invasive, safer biopsies with needles – in 30 percent of women with abnormal breast images.

I was truly surprised by this should-be outdated statistic, which further tips the mammography math equation in favor or screening. These numbers matter, and should be based in modern medical practice.

When the Annals of Internal Medicine published the since-adjusted recommendations for breast cancer screening by mammography in November 2009, the stated considerations were not about dollars and cents – which were incalculable – but about the number of women needed to be screened to save one life, and the incidence of false positives which cause harm – worrying, needless biopsies, complications of procedures, overtreatment, etc.

In the context of the health care reform discussion, and considering our country’s out-of-the-sky-and-rising medical bills, some (hopefully) well-intentioned economists heard about those trumped-up mammography papers and concluded that we shouldn’t screen women under 50 for breast cancer because it’s harmful and, what’s more, we can’t keep paying for this sort of care because it’s not evidence-based.

Those conclusions were flawed, though, because the data in those papers were old, as I’ve written previously, and didn’t include studies of digital mammography – which is better for detecting cancer in younger women who tend to have denser breast tissue. In December 2009, I noted that it was unreasonable to consider the costs of open needle biopsies in O.R.’s in any calculation of the harms of mammography, as had the Annals authors, because those kinds of procedures are outdated, or so I thought they were.

It turns out I’ve been living, still, in an academic medical enclave. According to the Timescoverage by Denise Grady:

The reason for the overuse of open biopsies is not known. Researchers say the problem may occur because not all doctors keep up with medical advances and guidelines. But they also say that some surgeons keep doing open biopsies because needle biopsies are usually performed by radiologists. The surgeon would have to refer the patient to a radiologist, and lose the biopsy fee…

The Times article suggests this pattern of over-doing open-biopsies, as documented in Florida, likely reflects national tendencies, including variation among different types of practices – academic, hospital-based, etc.

According to the article published in the American Journal of Surgery, the costs of a core needle biopsy using imaging guidance is around $5,000, or – if a vacuum biopsy device is used, around $6,000; the costs of an open procedure in the O.R. run in the range of $11,000 or more. The Times article indicates that doctors’ fees for a needle procedure range from $750 to $1500, and for an open, surgical biopsy from $1,500 to $2,500. For a ballpark estimate of the cost difference, say a core needle procedure is $5,500 + $1,000 for the doctor’s fees – that’s ~$6,500; a surgical procedure is $11,000 + $2,000 for the surgeon’s fees – that’s $13,000, an easy double.

So let’s say, for the sake of future calculations on mammography, that 10 percent of breast biopsies really do need to take place in the O.R. (which is a generous over-estimate, I think it should be 5 percent or fewer). But if 10 percent need be in the O.R.: then 20 percent of breast biopsies in the U.S. each year – said in the surgery paper to be 1.6 million per year in the U.S. – are being performed through an unnecessary, costlier technique.

An extra $6,500 x 20 percent of 1.6 million procedures = $2.08 billion additional costs, per year.

Let’s call it an even $2.1 billion, or $2 billion, we should shave off the collective amount we spend on mammography and appropriate follow-up. The last digit doesn’t matter; these are huge numbers. No wonder the Times put this story on the front page.

These results should be factored into any proper calculation of costs in breast cancer screening. Now add (or better, subtract) the implications of the findings of two weeks ago – that full lymph node dissection is usually not necessary in women, even if the sentinel node is found to be positive at the time of definitive surgery for what turns out to be a cancer.

What needs be reassessed by public health specialists and economists who weigh in on these issues – and please help me out here, Task Force members and Dartmouth friends, if you would, because your input affects public thinking and, ultimately, policy – are the legitimate costs of screening (every other year, as opposed to annually), doing needle biopsy procedures (instead of open biopsies) and reducing the costs and long-term complications of surgery by eliminating routine lymph node dissection from the equation.

And then we should assess those numbers relative to the costs of treating a woman with metastatic breast cancer, which still has not yet been determined.

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Stunning Comments on the Risk of Breast Implants, and Cancer

The FDA recently identified a link between breast implants and a rare form of lymphoma. From today’s report in the New York Times:

When talking to patients about a rare type of cancer linked to breast implants, plastic surgeons should call it “a condition” and avoid using the words cancer, tumor, disease or malignancy, the president of the American Society of Plastic Surgeons advised members during an online seminar on Feb. 3.

This is how doctors spoke to patients 50 and 100 years ago, and in some cultures still do, by not mentioning scary words – especially to women, and not calling a cancer what it is.

Cosmetic verbage?

Most cancers aren’t lethal* is one message for 2011: the “big  C” turns out to be a spectrum of hundreds of diseases, each with distinct subtypes, and patients shouldn’t panic when they hear the word. Some are benign in behavior although technically malignant; others behave live chronic illnesses; some, unfortunately, grow fast and can kill.

Oncologists can have a hard time persuading patients that a slow-growing tumor doesn’t need much treatment. It would help if other doctors don’t shy away from the term – keeping it taboo and, ultimately, promoting fear.

shhhhh

*NCI – cancer incidence and mortality summary data, accessed 2/18/11

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More News On Lymph Nodes and Breast Cancer Surgery

Last week the New England Journal of Medicine (NEJM) printed a major research article on lymph node dissection in breast cancer surgery. When I first saw the Times’ recent headline, I thought it would cover this paper: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer.*

It turns out there were separate articles on axillary node dissection after sentinel node biopsy in breast cancer – one in JAMA and one in the NEJM – published a week apart. For some reason, the NEJM paper got little attention in the media.

In the work reported in the NEJM, investigators based at the Univ. of Vermont evaluated if the presence of occult metastases – cancer cells found upon further examination of dissected lymph node specimens after the sentinel nodes were deemed negative – affects survival in women with early-stage breast cancer. What they found was that yes, it does: there’s a small but significant reduction in overall survival and disease-free survival at 5 years in women who have “negative” sentinel nodes but turn out, upon more detailed path inspection, to have some malignant BC cells in the armpit.

Kinda scary for someone like me, who had a negative sentinel node. The Vermont investigators determined that 16% of us have occult mets. Of those, 11.1% would be isolated tumor-cell clusters (less than 0.2 millimeters in greatest dimension), 4.4% micrometastases (between 0.2 and 2 millimeters) and 0.4% macrometastases (larger than 2 millimeters), all as classified by the American Joint Committee on Cancer.

On the other hand, the results were generally favorable all-around:

“The 5-year Kaplan-Meier survival estimates for patients in whom occult metastases were detected were 94.6% for overall survival, 86.4% for disease-free survival, and 89.7% for distant-disease–free interval; the survival estimates for patients in whom occult metastases were not detected were 95.8%, 89.2%, and 92.5%, respectively.”

Some details on the well-done study I feel compelled to insert here, a vestige of my thrice-weekly-journal-clubs-in-academic-medicine days:

The Vermont study is strong from a statistical standpoint: The researchers examined stored pathology samples from 5611 women with operable, clinically node-negative BC who were already registered in a large multicenter clinical trial (NSABP B-32). The study participants were randomized to receive either sentinel node dissection or sentinel node dissection followed by full axillary lymph node dissection.

It was a prospective analysis, and the median time on study was just under 8 years. Of the 5611 women enrolled, 3887 (~70%) had negative sentinel nodes and sufficient pathology material available for evaluation. Oncologists treating the patients were “blinded” to the data regarding occult mets, so that they wouldn’t be influenced in their treatment decisions. Among the women with negative sentinel nodes, 1927 underwent sentinel node dissection followed by axillary node removal and 1960 got sentinel node dissection only (based on the earlier randomization).

One result not emphasized in the paper was that removing additional nodes, after the sentinel lymph node exam, didn’t affect the clinical outcome in women with or without occult mets. This finding ties in with this week’s JAMA report, covered separately.

It’s a long article, probably of more interest to pathologists and BC oncologists than to the average reader here. There’s a lot interesting detail, including subtle results of planned subgroup analyses, on the prognostic significance of different kinds (sizes) of occult mets.

I know from my experiences – mainly lately as a friend of people with BC who, in the past few years since sentinel node studies have become the norm – that these issues regarding the significance of occult mets bear on everyday decisions patients make together with their oncologists: how much chemo to take?; should I get radiation to the axilla if there’s a tiny cluster of cells found?; should we add Taxol to the regimen? etc.

These are very real, every-day questions in oncology, and the answers aren’t obvious. But I do think the carefully-established findings reported in this paper will shed light, in an incremental sort of way, on how to best treat BC in women who have negative sentinel nodes at surgery.

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Breast Cancer Study Shows No Benefit In Extensive Lymph Node Removal

Today’s Times leads with a story on surgical removal of lymph nodes in women with breast cancer. The dramatic digital headline, Lymph Node Study Shakes Pillar of Breast Cancer Care, made me tremble at first glance. The article by Denise Grady covers a new report* in the Journal of the American Medical Association (JAMA).

The key finding is that for women with apparently limited disease before surgery who undergo subsequent radiation and chemotherapy, taking out all the cancerous nodes from the axilla (armpit) has no advantage.

I read the original publication and took some notes:

The randomized study, carried out by the American College of Surgeons, involved 891 women with early-stage breast cancer without palpable lymph nodes in the armpit. All underwent lumpectomy and sentinel lymph node examination that was positive – meaning that pathologists observed malignant cells in a sentinel lymph node. Half of the women underwent complete axillary lymph node dissection, by removal of 10 or more lymph nodes, and half did not undergo removal of additional nodes. All of the patients received radiation therapy and the overwhelming majority (>96%) got chemotherapy. The proportions of women treated with endocrine therapy were similar between the two treatment groups.

What the researchers found was that removing additional glands didn’t improve survival in women who had positive (involved) sentinel nodes upon lumpectomy. Survival was measured at 5 years, and the median follow-up was 6.3 years. There was no difference in overall or disease-free survival. This finding supports that for breast cancer patients who will have radiation and chemotherapy, it’s OK for surgeons to leave malignant lymph nodes in place rather than remove those by more aggressive surgery.

Why this matters:

In the majority of BC patients, the lymph nodes in the armpit are not noticeably enlarged at the time of diagnosis. But one in five will have a malignant node detected at surgery. Up until now the standard of care would include a complete axillary lymph node dissection in those women. This procedure can lead to lymphedema, a condition of chronic arm and hand swelling that can be painful and disabling. Lymphedema affects a small but significant fraction of the growing ranks of women – approaching 3 million in the U.S. – who are alive after breast cancer treatment.

According to the Times article, the new research findings could eliminate the need for axillary lymph node dissection in as many as 40,000 women in the U.S. each year: “The discovery turns standard medical practice on its head.”

I’m not so sure I’d go so far as saying that – mainly because I don’t find the results surprising. But I do think it’s a study that matters: The implications bear on costs of breast cancer care (and, yes, on the “costs” of mammography and finding BC) and should have a positive effect on the quality of life for millions of women living after breast cancer treatment. There’s the potential to reduce surgery, and its complications, for the majority of new breast cancer cases.

Why aren’t the results surprising?

Breast cancer treatment, and our understanding of breast cancer biology, has advanced steadily in the past 25 years.

Now it’s routine to give treatments – like chemotherapy, hormone modulators or antibodies like Herceptin – that target breast cancer cells where-ever they reside in the body. The whole point of adjuvant therapy is to destroy malignant cells remaining after surgery. If there are some residual lymph nodes with malignant cells in the armpit region, those would likely be destroyed by chemotherapy and other treatments, combined with radiation to the affected chest and underarm area.

What are the study’s limitations?

What’s not adequately addressed is the situation for women who undergo mastectomy and don’t get radiation, as is standard after lumpectomy.

Another limitation is the study’s relatively short follow-up, of just over 5 years. This is a valid concern in any study of BC survival, but my own opinion is that the axillary node intervention is unlikely to result in a big difference later on. That’s because in 2011 what matters most for treatment decisions, after diagnosis and initial surgery, is the nature – in terms of genetic and molecular features – of the malignant cells.

It happens the NEJM ran a relevant paper on sentinel node dissection last week; we should explore those findings, tomorrow.

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Pink’s OK With Me

On Sunday, Feb. 20, the Northeastern Pennsylvania Affiliate of Susan G. Komen for the Cure will host its seventh annual Pink Elegance on Parade fashion show at the Radisson at Lackawanna Station hotel, reports the Scranton Times Tribune. The fundraiser will feature breast cancer survivors and others modeling fashions from Coldwater Creek, Lee’s Denim Diner, Luna Bleu and Suburban Casuals.

Portrait Of A Lady In Pink Ribbons, by Raimundo Madrazo (Wikimedia Commons)

Some BC survivors, thrivors, thrivers, in-the-throws-ers and whatever we might call ourselves (I still can’t make up my mind on this) express disdain. Others, lately, convey cynicism, if not frank contempt, for the pink cancer culture in its entirety.

Pink is tacky, pretty and possibly too rosy a color to link with the fate of so many sick and dying women. I half-agree. But then again, I’ve never favored pastels: I’m a brown and gray sort of woman. When I’m feeling cheery, I wear navy or maybe mauve. This is not a policy statement; it happens those hues match my skin tone and nature.

Yes, I and others have written that it can be off-putting, that it clouds and distracts us from the reality of cancer. But it takes a certain confidence to don a magenta outfit and not feel silly or excessively feminine (if there is such a thing), as I would, regardless of one’s BC status or awareness level. So I give women credit for wearing pink. And I’m half-envious, besides.

If you’ve had breast cancer and wear pink – why not? I fear the anti-pink movement is making people feel bad about wearing pink to show support for breast cancer awareness, fundraising and related issues. Which is ridiculous. People with breast cancer and their supporters should wear what they want and do as they please, at least wardrobe-wise.

So all power to you, women in Scranton and BC fundraising friends! Show off those post-treatment non-breasts. Be pretty in pink, and proud!

And I’m sure you won’t mind if I wear gray. In the end, isn’t this about supporting one another, and tolerance?

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An Oncologist Considers Rare Lymphomas in Women With Breast Implants

I have to admit that when I first read about the FDA’s report tying rare cases of anaplastic large cell lymphoma to breast implants, my mind raced with a strange blend of excitement, intense interest and concern. My thoughts shifted from “wow, that’s really interesting” to “exactly what did the FDA find” to “should I be worried?”

So I’ve decided to write this morning’s post from my perspective as an oncologist who spent roughly 15 years of her life studying the causes of lymphomas and related blood malignancies. Some readers of this blog, who fortunately at this point in ML’s slow-but-steady growth are mainly strangers, may be unaware that understanding rare lymphomas was what I lived for in my research work, which occupied the bulk of my time and thought, which I loved very much (as strange as that may seem to some) and which I miss intensely, still, today.

The reality, as very-carefully documented by the FDA in its excellent analysis (which, in my opinion, far surpasses that of most case series reported in the medical literature; I’d give the agency an A+ for detail, thoroughness, clarity and openness about the limitations of the findings thus far), is that these cases of ALCL are few and far between: a total of 60 cases, worldwide, as I reviewed in yesterday’s post. Sometimes just a few cases are indicative of a problem, and I think that is exactly what’s going on with these rare lymphomas.

The pathology is interesting: Essentially all of the ALCL cases are T-cell derived and express CD30. Anaplastic lymphoma kinase (ALK) was negative in each of 26 cases examined for that receptor. The findings are plausible in the context of an aberrant immune response – which can occasionally become malignant – to a foreign body or particular antigen associated with the implants. These oddly uniform characteristics among these rare lymphoma cases support that the FDA’s findings are not random.

Most of the ALCL tumors were limited to the area of the implant capsules, and could – as best I can tell from the few reports – be treated by removal of the implants and affected, adjacent breast tissue. These don’t appear to be aggressive lymphomas, as are some ALCL’s. I would go as far as to speculate that these might indeed be antigen-driven tumors; in this light, it would make sense in principle and in practice to treat these by removal of the implants, at least as a first-line approach.

So if I had a patient with this condition, I’d tell her that these lymphomas are very rare and, when they do arise, can usually be treated by removal of the implant. But I wouldn’t down-play the risk, which is tiny but real.

As an oncologist, I found most of the coverage of the FDA’s alert disappointing, the discussion dominated by plastic surgeons’ reassurances and device makers’ dismissals. Statements like “a woman is more likely to be struck by lightning than get this condition” – proffered by an Allergan spokeswoman as quoted and emphasized in the WSJ Health Blog, Bloomberg News, LA Times and elsewhere – are not helpful to women with implants who are genuinely concerned about their health.

Because I understand that once a woman has had one form of cancer, her risk of developing another tumor is elevated – from whatever genetic, environmental or other disposition she has for malignancy, and from treatment toxicity. Most of the women I’ve seen with implants after mastectomies have some problems considered minor – like thickening of the capsule and dimpling in peri-implant tissue. But these are the exact sort of abnormalities as described in the FDA’s alert, for which there is now a recommendation: evaluate and report cases to the FDA.

Ultimately this is an issue about informed consent – and I don’t mean by this the paperwork, but the reality of women with choosing, or not, to get breast implants. Doctors need more information about these rare lymphomas: how often these arise, why they occur, and how they should be managed so as to cause the least harm when and if treatment is necessary.

The FDA provides a helpful list of sources, from which I’ve selected those that seem most relevant (see reference page). Of historic interest, also, is a NEJM perspective from 15 years ago on the debate about rheumatologic illness, the public’s perception and risks associated with breast implants.

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FDA Reports on Association of Breast Implants and a Rare Form of Lymphoma

Yesterday the FDA issued an alert about a possible link between breast implants – saline or silicone – and a rare form of lymphoma called anaplastic large cell lymphoma (ALCL). These lymphoma cases are exceedingly rare, but the association appears to be significant.

The FDA identified a total of approximately 60 ALCL cases in association with implants, worldwide. Of these, 34 were identified by review of published medical literature from 1997 to May, 2010; the others were reported by implant manufacturers and other sources. The agency estimates the number of women worldwide with breast implants is between 5 and 10 million. These numbers translate to between 6 and 12 ALCL cases in the breast, per million women with breast implants, assessed over 13 years or so.

In women who don’t have implants, ALCL is an infrequent tumor, affecting approximately 1 in 500,000 women is the U.S. per year. This form of lymphoma – a malignancy of lymphocytes, a kind of white blood cell – can arise almost anywhere in the body. But ALCL cases arising in the breast are unusual. The FDA reports that roughly 3 in 100,000,000 women are diagnosed with ALCL in the breast per year in the U.S.

These are very small numbers. Still, the finding of ALCL tumors by the implant capsules is highly suggestive. Almost all of the implant-associated ALCL cases were T-cell type, whereas most breast lymphomas are of B-cell type. The lymphomas arose in women with both silicone and saline-type implants, and in women with implants placed for purposes or augmentation and for reconstruction after mastectomy.

The clinical features varied among the reported cases. From the FDA’s review:

… the median time from breast implant placement to ALCL diagnosis was 8 years, with a range from 1 year to 23 years. Most patients were diagnosed when they sought medical treatment for implant-related symptoms such as persistent seromas, capsular contractures, or peri-implant masses warranting breast implant revision operations. In each case, lymphoma cells were found in the effusion fluid (seroma) surrounding the implant, in the fibrous capsule, or within a peri-implant mass. Typically, there was no invasion beyond the fibrous capsule into the breast parenchyma.

Figure 1 illustrates the location of the reports of ALCL adjacent to the breast implant.

This illustration shows the breast implant placed under the skin and breast tissue. The implant is separated from the breast tissue by a fibrous scar capsule. ALCL lymphoma cells are shown in the effusion fluid between the breast implant and the capsule and attached to the capsule itself.

Figure 1. Presence of ALCL cells in close proximity to a breast implant. In most cases, the ALCL cells were found in the effusion fluid (seroma) surrounding the implant or contained within the fibrous capsule. ALCL is lymphoma, a type of cancer involving cells of the immune system. It is not cancer of the breast tissue, and typically, invasion of the lymphoma beyond the fibrous capsule into the breast parenchyma was not observed. Modified from Thompson et al, (2010).

With such a small number of cases worldwide, it’s hard to draw evidence-based conclusions regarding the appropriate treatment of these rare lymphomas. More from the FDA:

Treatment was reported for 20 patients. Most had the implants removed, and some went on to receive treatment with radiation and/or chemotherapy. Overall, the outcomes appeared to be more favorable than would typically be expected for systemic ALCL. Outcomes were reported for 19 cases. Of these, 14 patients had no evidence of disease at last follow-up. However, most cases were diagnosed with early stage disease, and follow-up on many cases was limited.

At this time, the FDA is advising health care providers to be aware of the possible diagnosis, to carefully evaluate breast implant patients with suspected ALCL, and to report all confirmed cases to the agency.

As for patients, the situation is troubling. The incidence of these tumors is quite low, almost immeasurable, and the prognosis – based on the few treatment reports – seems good. But many women do have some fluid, contractures, thickening and other complications around the implant capsules. Most of those physical aberrations surrounding the implants are not lymphoma.

It’s a Pandora’s box, but one that needs be opened. The problem is that if we biopsy every abnormality – such as a minor thickening or fluid accumulation adjacent to a breast implant – we’ll hike up the costs and, more importantly, the complications associated: With every needle stick there’s a risk of infection, additional scar formation and more. On the other hand, you wouldn’t want to overlook a treatable, early-stage lymphoma. Women need to know of the risks of implants, which can only be determined if doctors thoroughly investigate these sorts of complications.

The LA Times quotes Dr. Phil Haeck, president of the American Society of Plastic Surgeons: “I think there’s reason to be concerned about this, but there shouldn’t be reason for panic,” he said. According to that article: “Signs of ALCL associated with implants ‘are pretty dramatic. There’s a lot of swelling and pain. They won’t miss it,’ Haeck said.”

I’m not so sure. Lymphoma, including ALCL in my experience as an oncologist, can be very subtle.

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