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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Good People, a New Play About Chance, Decisions and Fate

A short note on Good People, the title of a new play at the Manhattan Theatre Club starring Frances McDormand

It’s a simple story, at some level, about a middle-aged woman from south Boston who loses her job. She has a disabled, adult daughter who needs caregiving, and she needs money. She contacts some old friends, and scours the neighborhood for a job. She encounters a once-boyfriend, just for a summer at the end of her childhood, who’s become a doctor with a fancy office and a fancy house and a beautiful wife.

Frances McDorman, in a photo for the MTC

And she’s angry, angry because she’s never been able to leave her community despite, as she puts it, “being nice.” She put her daughter’s needs first and helped others when she could – or so she says, but she was too often late for work at one job and the next, because she was waiting for the daughter’s sitter, or because she couldn’t pay the bill on her car, or for some reason or other unfortunate event, as she sees it, that isn’t quite her fault.

The play’s well-executed, with firm acting and revealing details – like the wallpaper and mismatched furnishings  in the woman’s kitchen, and the spotty sportswear the women don when they go out to be sociable. Some scenes take place in a church, where the characters chat as they play “BINGO,” waiting and hoping for a lucky break.

It’s about fate, and responsibility, and assumptions people sometimes make. And it’s closing this Sunday.

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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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Noting Depression in Susan Glaspell’s 1917 Story: A Jury of Her Peers

Recently I read the short story, A Jury of Her Peers by Susan Glaspell, with a group of women in my community. The author, with whom I wasn’t previously familiar, first reported on the real 1901 trial of Margaret Hossack, as a journalist writing for the Des Moines Daily News. Later she adapted the story as a one-act drama, Trifles, and then in 1917 as a short narrative published in Everyweek, a long-defunct magazine of the Crowell Publishing Company.

Original performance of "Trifles," (from the Billy Rose Theatre Collection, New York Public Library at Lincoln Center)

There’s a lot you might take from this swift, rich read. It goes like this: A man and his son came upon a couple’s house in rural area. The man’s been killed, clearly; his wife sits in a chair, oddly, and can’t say what happened to her husband. The local authorities and a few neighbors step in. The home was not well-kempt; the wife is accused of murder. Two other women, whose words spin the tale, poke about the kitchen and make inferences about the jailed woman’s circumstances.

Some points are readily gleaned: on homemaking, and quilting – literally and metaphorically, in early 20th Century America. There are legal elements, and allusions to domestic violence and abuse. What intrigued me most, though, was the author’s indirect depiction of their neighbor’s isolation and apparent depression:

“A person gets discouraged–and loses heart,” one considers…

“I stayed away because it weren’t cheerful–and that’s why I ought to have come,” says the other.

The two women express sympathy for the accused wife’s plight; they regret that they didn’t visit or otherwise help her earlier on, before the situation took a catastrophic, violent turn. The women understood, without saying it exactly. Mental health wasn’t a topic of common discourse, then, but these characters – and so must have the author, clearly – got the drift.

I won’t tell the whole story here, but I do recommend the tightly-woven, knotted piece.

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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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Tennis News and Why a Healthy Young Woman Might Get a Pulmonary Embolism

Yesterday I learned that Serena Williams, the tennis pro, has been treated for a pulmonary embolus. My husband found out this morning upon reading the newspaper. He wondered why this would happen to a strong, young, athletic woman.

Without delving into the private or specific aspects of her case:

A pulmonary embolism, or PE in doctor-speak, happens when a blood clot enters or forms in the blood supply to the lungs. It’s a serious condition, because when blood vessels in the lungs are compromised, the lung cells can’t deliver fresh oxygen to hemoglobin that would normally pass through in red blood cells. Symptoms sometimes but not always include shortness of breath, pain in the chest that’s sharp in quality, and fatigue. Usually the diagnosis is made by a scan, such as a VQ or a special kind of (spiral) CT.

tennis racket and ball (Wikimedia Commons)

Treatment includes a blood-thinner, usually for a period of months. At first, and depending on the severity of the circumstances, patients may benefit from oxygen treatment through a light face mask or by nasal prongs. In general, doctors monitor patients for a short time in a hospital, to make sure the clot doesn’t get worse and that they don’t need additional oxygen support, and that the anti-coagulant is working.

When patients get blood clots it’s usually because they have a genetic tendency combined with some situation that aggravates that disposition. For example, if someone is born with a deficiency in a protein – of which there are quite a few – that normally dissolves clots, they might feel fine throughout life and be unaware of their hypercoaguable state. But after a big surgery, or if they were immobilized and dehydrated on a long plane ride, that might lead to a clot formation.

Sometimes surgery or inflammation in an extremity, such as a leg, can dispose to clot formation. When a clot forms there, it’s called a deep venous thrombosis (DVT) and that can, especially if untreated, break off and move through the large veins, to the right side of the heart, and then enter the pulmonary artery and smaller vessel or vessels in the lung. In that case it’s a PE.

Pregnancy, in itself and especially in women with underlying clotting disorders, can dispose young women to a DVT or PE. The same is true for estrogen-containing medications including birth control. Smoking, too –

A short personal perspective is that I once cared for a woman who had a PE who was young and attractive. She had been on a long, international flight a few days before she came to the E.R. It took hours for her to get past triage, and I suspect that was because she looked so healthy. It turned out she had a huge clot in her lungs, and a complex clotting disorder.

If a person with a DVT or PE turns out to have a genetic disposition, it doesn’t mean they need life-long treatment with a blood thinner. Depending on the location, severity of the clot and the circumstances, treatment is given for weeks or months. But it can be helpful to know if you have a clotting disorder. Some patients take prophylactic, low-doses of blood thinners when they travel or after immobilizing surgery, like a hip replacement.

Here are some useful websites that provide information on blood clots:

The American Society of Hematology (which confirms that March is DVT Awareness Month)

PreventDVT.org

Medline Plus

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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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Another Brooklyn (and how I feel when I look in the mirror)

The image of Brooklyn Decker, a real woman and model from Middletown OH, streamed through my Google news feed this morning. I have to admire any person named Brooklyn, the place where I was born.

From a post on my BlogHer health RSS:

Brooklyn Decker on the cover of Sports Illustrated, in 2010

The BlogHer subject is Decker’s diet and exercise secrets: “…no matter how wealthy or famous you are, Decker says the only thing that really works is exercise, eating healthy and accepting your body for what it is that will make you succeed.”

Got it.

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After Breast Cancer, Get a Gym Membership!

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

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

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

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

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

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

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

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

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

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

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Does Cathy Make the Right Cancer Treatment Decision in the Big C?

scene from season finale, The Big C

“I don’t want to get sicker trying to get better and then just end up dying anyway” – Cathy, the 42 year old protagonist with advanced melanoma, on the Big C.

ML’s incoming search data suggest that some people out there are very determined to know exactly what happens to Cathy in Showtime’s new series about a young-seeming, middle-aged woman with advanced, presumably stage IV, melanoma. In last week’s review I elected not to give it away. Now I’ve reconsidered. So here’s a spoiler alert: Don’t read this post if you don’t want to know what happens to Cathy at the end of the Big C‘s first season.

After months of unusual and comfort zone-breaking behavior, Cathy reconsiders her initial decision to forgo treatment. She, possibly influenced and clearly supported by her husband’s enthusiasm for her middle-aged life and continued existence, indicates that she’s willing and ready to try treatment with Interleukin-2. Cathy seems to know something about the FDA-approved drug, which is generally toxic and ineffective in most melanoma cases. At one point, she lists its putative side effects, according to the show: “burning scabs all over my body, constantly throwing up, fluid on the lungs, my veins could shut down, I could die on the table…”

Nonetheless she decides to accept treatment:

“I’m gonna hang on as long as I can. And I’m going out ugly,” says Cathy, played by the actress, Laura Linney.

“It will never be hard for me to look at you,” responds her supportive husband Paul, portrayed by the actor Oliver Platt.

At this point Cathy’s hoping the Interleukin-2 (“interlaken,” as her husband keeps calling it, perhaps metaphorically, subconsciously, or else just simply) will keep her alive for six months, when she might or might not be eligible for an experimental anti-melanoma drug in a clinical trial.

So she goes for it: in the final scene she’s in the hospital, her mind cloudy, and dreaming. You may wonder what I think of her decision.

As an oncologist I’m half-relieved. The patient will, undoubtedly, die too soon – within months or a year or, if she’s lucky, maybe two years or even longer – because you never really know for sure about these things, if she doesn’t take any treatment. Deaths from metastatic cancer can be unpleasant and painful. On the other hand, conventional therapy for stage IV melanoma rarely leads to complete remissions and, essentially, never cures the disease.

I admired that the patient, until this last episode, maintained such a no-nonsense approach to her condition. Her perspective seemed more mature than her oncologist’s. Despite her weird and nearly unraveling behavior, she’s clearer in her priorities than many patients I’ve known; she seems to understand that a treatment might give her a few additional months but is very unlikely to help her get well and, likely, would make her sick for the duration of her life.

Sometimes oncologists get carried away with hope. What I liked best about the story is that she, the patient, was realistic in this. She didn’t want to take toxic medications in desperation, without reason.

As a patient, my feelings are mixed, too. I respected Cathy lack of passivity in her decision. Accepting treatment initially would have been the easier, “normal” thing in our culture. In effect, so far, Cathy’s taken control of what happens to her body. At the same time, I couldn’t help wonder – what if she tried it? Maybe there is a cure in the pipeline, and she’d be eligible for an experimental agent in a few months, and that drug would help her, and she’d live beyond middle age, or at least until she’s 45 or 46.

Today is Monday, but there’s no new Big C episode because the season’s over. We won’t know how Cathy fares with the Interleukin-2 for a while. Even though she is just a cable TV character, she’s in a position to teach us about oncology and living with cancer.

Hopefully the show’s producers will provide insights into immune treatments, targeted agents, clinical trials, informed consent and palliative care. (I will consider Interleukin 2 and melanoma in a separate post, to follow.) But given the TV scenario, do you think Cathy’s made a sound decision?

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First Season Ending of the Big C

Last night I stayed up late to see the season finale of the Big C. For the first time in watching this series about a 42 year old woman with advanced melanoma, in a near-final scene involving the protagonist Cathy’s teenage son, I cried.

The storyline is moving, finally, in a real and not necessarily happy direction. I must admit I was disappointed overall with the program overall until lately. That’s not because Cathy behaved recklessly and irresponsibly upon receiving her Stage IV cancer diagnosis – her decisions are her personal business and a plus for my engagement. At least the program’s not too preachy.

My gripes are with the show’s other confused characters: her homeless brother, in a TV relationship with Cynthia Nixon’s spent, post-Sex in the City character, is so extreme in his strangeness, choosing not to shower for instance, he distracts from the narrative; her obese student, played by Gabourey Sidibe, seems like she’s stuck in the wrong program; her “oncologist” is so free with his time, and apparently has so little else to do (how about studying for his boards, if he still hasn’t any other patients besides Cathy?),  he comes across as a joke instead of as a credible and sensitive physician who’s completed his training.

The good news of course is Cathy, played fantastically well by Laura Linney. She’s amazing, perhaps more than ever, a good example of how women don’t have to be knock-out gorgeous to shine. Phyllis Somerville, as Cathy’s crotchety old neighbor Marlene, offers a revealing image of loneliness and dementia, with a bit of paranoia thrown in her mix. The two men in Cathy’s life – her husband and recent lover – provide a strange balance that somehow works around her: the lover is nice, supportive and easy-going; her husband is intense and devoted; his uber-love is persuasive. As for Cathy’s son, well, he’s grown on me over the past few months.

My favorite scene, easily, is Cathy dancing with a way-alternative cancer treatment provider, the Canadian “bee man” portrayed by actor Liam Neeson. How sad he must have felt, on the set, holding close a middle-aged woman in the role of someone facing death in slow-motion.

I don’t want to give the plot away, so I’ll just say that I will definitely keep watching the Big C. I can’t wait to see what happens with Cathy, if she’ll make it to the clinical trial that opens in six months and if she’ll be eligible for experimental therapy. This is no ordinary TV show.

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A Play About the Life and Work of Dr. Rosalind Franklin

Last weekend I snagged a last-minute ticket to see Photograph 51, a new play about the work and life of Rosalind Franklin. Her data, possibly stolen, enabled Francis Crick and James Watson to decipher and model the double-helix structure of DNA.

The intimate production, enacted by the small Ensemble Studio Theatre on the second floor of a nondescript building on West 52nd Street, affords a fresh look, albeit partly fictionalized, into important moments in the history of science. Most of the scenes take place in a research lab in post-War London, at King’s College, where Franklin took on a faculty appointment.

Franklin’s story starts like this: She was born in 1920 to a Jewish family in London. She excelled in math and science. She studied physical chemistry at Cambridge, where she received her undergraduate degree in 1941. After performing research in photochemistry in the following year on scholarship, she joined the British Coal Utilisation Research Association (BCURA) and carried out basic investigations on the micro-structure of coal and carbon compounds, and so earned a Ph.D. from Cambridge University. She was a polyglot, and next found herself in Paris at the Laboratoire Central des Services Chimique de l’Etat, where she picked up some fine skills in x-ray crystallography.

You get the picture: she was smart, well-educated and totally immersed in physical chemistry before, during and after WWII. Single-minded and focused, you might say –

Franklin in Photograph 51 wears a simple brown dress with large black buttons straight down the middle of her lithe frame. Her lipstick and haircut seem right, but her three inch heels, even after a few years of experiencing the joie de vivre in Paris, or just being holed up in a research institute there, seem a tad too high for such a pragmatic soul. The lab set is perfect with its double-distilling glassware, wooden pegs on racks, tall metal stools with small, flat circular seats, light microscopes, heavy metal desks with file drawers and a contentious cast of characters.

As this narrative goes, Franklin spurns socializing with most of her colleagues. They find her difficult. She spends nearly all of her time and late hours using x-rays to generate crystallographic images of DNA and making detailed notes and related calculations. Eventually a lab assistant gives her key data, Photograph 51, to her colleague, Maurice Wilkins, who is inexpert in crystallography and cannot independently interpret the structure. While Franklin continues working at a measured pace, refusing to rush into publishing a model until she’s sure of her findings and the implications, Wilkins shares the image with Watson and Crick. They move quickly, publish first in Nature and, later, win the Nobel Prize for the discovery. Meanwhile Franklin leaves Wilkins’ lab and starts a new project on the structure of tobacco mosaic virus. She dies at the age of 37 of ovarian cancer, likely caused or effectuated by the radiation to which she exposed herself at work.

It’s a sad story, but instructive, engaging and very well-done, so much that it’s haunted me for days. Hard to know what’s real –

According to a program note from Anna Ziegler, the playwright: “this play is a work of fiction, though it is based on the story of the race to the double helix in England in the years between 1951 and 1953.” Ziegler refers to several books from which she drew material: The Dark Lady of DNA (by Brenda Maddox), The Double Helix (by James Watson) and The Third Man of the Double Helix (by Maurice Wilkins).

My favorite part is Franklin’s statement at the beginning: “We made the visible, visible.”


For a (depressing) counterpoint to this play’s version of events, you can take a look at Nobel Laureate James Watson’s 2007 TED lecture on YouTube. “She was a crystallographer,” he says of Franklin, and other things, before delving into his late-life happiness and current ventures in cancer genetics and autism studies.

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New Findings on Postmenopausal Hormone Replacement Therapy and Breast Cancer

This week the Journal of the American Medical Association (JAMA) published results of a large study with significant implications for women who consider taking hormone replacement therapy (HRT). The new findings are based on careful examination over 16,000 individuals, part of the larger Women’s Health Initiative, who were randomly assigned to take either a placebo, or Prempro – a combination pill that includes estrogen, extracted from equine (horse) urine, and medroxyprogesterone acetate, a synthetic progesterone compound.

The extended data confirm that women who take hormone replacement therapy are more likely to develop breast cancer than those who don’t take it. But this finding has been seen previously, and was one of the reasons why the randomization was halted earlier on –

What’s new is that the breast cancers in women who took hormone replacement therapy are more invasive, with greater extension to the lymph nodes, and more deadly. Women ages of 50 to 79 years who take hormones are roughly twice as likely to die from breast cancer as those who don’t take hormones, and are more likely to die earlier, of any cause.*

In 2002, JAMA published a landmark report on an earlier analysis of the same trial, which was halted because of the evident toxicity, then, of hormone replacement therapy. Before that time, the treatment was thought – on theoretical grounds – to reduce the risk of heart disease.

The drugs were marketed heavily throughout the 1990s, particularly through gynecologists and primary care physicians, and later to women directly – an “ask your doctor” kind of thing. In tangible ways, these drugs tend to make women feel younger and suppler, with fewer hot flashes. Many women I knew were eager to try these hormone supplements.

My perspective is that of an oncologist. Knowing that most breast cancer cells have receptors on their surfaces for estrogen and progesterone – steroid hormones that stimulate growth of normal mammary (breast) tissue cells in healthy women – the findings seem entirely plausible. . Besides that the hormones can bind receptors on cancer cells’ surfaces and trigger growth pathways, there may be other effects. The authors of the new JAMA article suggest, for example, that the hormones can enhance the blood vessels that “feed” breast tumors, and so might make them worse.

Denise Grady provides a thorough report in the Times on this topic. As she points out, approximately 3 million women in the U.S. still take hormone replacement therapy. Before the 2002 report, as many as 6 million postmenopausal American women were prescribed this kind of medication. The incidence of breast cancer in North America has declined since 2002, and most oncologists and epidemiologists ascribe much of that improvement to reduced use hormone replacement therapy.

Still, many doctors still prescribe hormone replacement therapy. There’s a huge potential market for these drugs, and so a lot of money’s at stake, besides women’s health. Based on U.S. census data from 2000, the number of women between the ages of 50 and 79 approached 40 million and, today, is likely larger still.

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*The absolute numbers run like this:

Among the 8506 women randomized to take hormone replacement therapy (HRT), there were 385 BC cases detected; among the 8102 assigned to placebo, there were 293 cases identified. (This was a statistically significant difference.) These numbers can be whittled down, then, to a total of 678 BC cases – out of 16,000 women on the trial – who developed BC. The pathology was similar between the two groups, in terms of molecular subtypes. But the invasiveness – in terms of lymph node involvement – was higher in the HRT group, as was the mortality: 25 women died from BC in the HRT group; 12 women died from BC in the placebo group. (This was also significant, but with a p value of just 0.049).

One caveat, or limitation, to the study is that the authors didn’t have access to detailed information on the women’s treatments, which may or may not have differed between the groups. A strength of the study is the relatively long follow-up, of 11 years on average.

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Five Ways to Improve the Quality and Success of Breast Cancer Screening by Mammography

Here are some ideas on how we might reduce the incidence of metastatic breast cancer, by making high-quality mammography available to all women:

1. Modernize all breast imaging facilities. All should comply with the Mammography Quality Standards Act and Program (MQSAP) of 1992.

2. Ensure that radiologists, technicians and other BC screening workers are up to date: requirements for continuing medical education in an academic, unbiased (non-pharma or biotech setting), should be strict. We depend on practitioners’ current knowledge of breast imaging methods, breast biopsy techniques, hygiene, information technology (IT) and patient privacy laws.

3. Implement digital mammography in all screening facilities; Digital images allow radiologists to adjust the contrast, magnify or otherwise highlight areas of concern, to better analyze potential lesions without subjecting patients to extra x-rays.

4. Supplement mammograms with sonograms of the breasts. These inexpensive tests can help radiologists discern cysts and other benign lesions from malignant tumors. In some situations, a radiologist inspecting a sonogram can spot a small solid abnormality that’s missed in a mammogram. In principle, this low-rad combo – of digital mammography and breast sonography – would increase sensitivity and specificity of breast cancer screening.

(5.) Consider transmitting digital images to breast screening centers, so that expert radiologists can review every woman’s films.

As Sue, a woman who’s had breast cancer told me last month: “You don’t want a radiologist who’s just looked at someone’s broken foot examining your mammogram.” She’s right: Expertise can make a huge difference in clinical outcomes.

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Why I Went for My Screening Mammogram

Dear Readers,

This week marks eight years, exactly, since I had an abnormal mammogram that led to my breast cancer diagnosis. I was 42 years old, and lucky because the excellent radiologist who discovered my tumor was a super-specialist in breast imaging, the kind of radiologist who spends her work-time analyzing mammograms, performing breast sonograms and taking biopsies of suspicious lesions. She doesn’t often look at hip films or ordinary x-rays. She just does mammograms, mammograms and mammograms, and sometimes additional tests to evaluate abnormalities she detects in those. She knew her stuff.

I was afraid to get a mammogram because I didn’t want to learn I had cancer. Back then, my breasts were so glandular it was hard for me, an oncologist, to discern what might be a pathological lump, or not. I feared having a “false positive,” and undergoing multiple tests to evaluate abnormal images that would turn out to be nothing but big-bill inducing benign lesions.

Really I was hesitant in visiting her office. I didn’t have time for cancer, because I was in pain from a crumbling spine and needed to get my back fixed before even opening up the possibility of additional medical problems. I wanted to work as much as I could then, before and after that big reconstructive spinal surgery, so that I might continue research and publish more papers. Besides, my sons were young then – ages 8 and 10 – and I didn’t want to not be able to make dinner because I was throwing up, or die.

Not getting a mammogram was a way of not finding out. The shoemaker’s kids don’t get shoes. An oncologist doesn’t get a mammogram…

My general internist, whom I trusted, insisted that I go for screening. “You’re over forty, you know,” she said. But I had no family history of the disease, then – this has since changed, and I didn’t consider myself at increased risk. Ultimately I went for the mammogram because I knew it was the responsible thing to do, to take care of myself.

When I had the mammogram, and the sono to evaluate an abnormality, and the core needle biopsies in the next week, I wasn’t afraid so much as I was annoyed by all the inconvenience. “Who has time to be a patient?” was my attitude. I came to each doctor’s appointment armed with research articles and colleagues’ manuscripts to review. I had meetings to attend, and responsibilities, and participated actively in a typical two-career family kind of up-and-out-early way of raising our sons.

All of that is behind me now, as is the chemo,  hair loss, some incidental fractures, surgeries, generalized fatigue and sad times that followed. How lucky I am that I went that day. There is no doubt in my mind.

Next year, approximately 45,000 women in the U.S. will die of metastatic breast cancer. Why I advocate for screening mammograms is because I know that a significant fraction of those advanced cases, perhaps half or more, could be prevented by early detection. That benefit would be a boon to the public health: perhaps as many as 20,000 – 30,000 women spared per year from morbidity, suffering and mortality of metastatic breast cancer, which is currently an incurable, costly disease.

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Why It’s So Hard to Assess False Positives, and How We Might Reduce Them

It’s been nearly a year since we “learned” about the false positives issue, and still there’s hardly any data published on this much-maligned cost of breast cancer screening by mammography.

From the U.S. Preventive Services Task Force November 2009 paper in the Annals, on the lack of information on the incidence of  FP’s:

“Published data on false-positive and false-negative mammography results, additional imaging, and biopsies that reflect current practices in the United States are limited. The probability of a false-positive screening mammography result was estimated at 0.9% to 6.5% in a meta-analysis of studies of sensitivity and specificity of mammography published 10 years ago <ref. 38>. The cumulative risk for false-positive mammography results has been reported as 21% to 49% after 10 mammography examinations for women in general <39–41>, and up to 56% for women aged 40 to 49 years (41)

False positives happen in mammography when a woman has an abnormal result that looks like it might be breast cancer, but upon a further workup – which might involve another, more expert radiologist taking a look, or a sonogram, or an MRI, or even a breast biopsy, but in the end the problem turns out not to be breast cancer.

Why is it so hard to ascertain how often false positives occur?

1. The rate of false positive mammograms is, most likely, declining (i.e. the number is in flux).

Reduced errors would result from two factors: improved methods, such as by adaptation of digital mammography, and by more careful application of extant technology due to progressive compliance with the FDA’s Mammography Quality Standards Act and Program.

2. There’s no precise definition of what constitutes a false positive in mammography, and what isn’t. As I’ve suggested previously, finding a pre-malignant condition like LCIS or an early-stage malignancy like DCIS should not be “counted” as a false positive. If over-treatment occurs, that reflects an error in clinical decision-making rather than in mammography, per se.

3. The false positive rate varies among radiologists and medical centers. That’s because a radiologist who spends her days doing nothing but reading mammograms and breast sonograms will, overall, have a lower FP rate than a general radiologist who also handles hip fracture films and MRIs of the brain.

What are financial costs of false positives? I’m not aware of any new data on this.

How can we reduce the costs of false positives in mammography? My suggestions:

1. Radiologists should be well-trained and carefully-credentialed. As in surgery and other fields in medicine, the physician’s skills and experience affects the probable outcome.

2. Avoid doing breast biopsies in an operating room whenever possible. A fine needle aspirate or core needle biopsy, performed under local anesthesia, is almost always sufficient for diagnosis and less costly.

3. Thinking for the future: Maybe, one good application of Telemedicine would be in sharing digital mammography images, so that no matter where a woman lives, her test could be checked by a radiologist working in a central cancer center and who specializes in breast imaging.

4. Do the procedure every other year for women of average risk for breast cancer (rather than annually). Quite a few theoretical calculations of mammography costs “stack” the purported costs by assuming the procedure is done every year, but there’s no data to support such frequency.

In sum, there’s every reason to think the rate of false positives in screening mammography is falling and that costs from errors will diminish in the future.

Many, if not all, of the costs attributed to false positives will be reduced by advances in technology, better training of radiologists, and education of physicians (oncologists, surgeons, primary care physicians) who recommend the procedure and make decisions based on the results.

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A Visit to Suffragette City

For two days I’ve been traveling on a short road-trip with my family in Upstate New York. As far as this turning to a medical lesson, all I can say is that for the first time in my life I witnessed, first-hand, the vaguely digital, elongate and eponymous geography of the fine Finger Lakes.

morning view, by Seneca Lake

It’s beautiful around here. I’ve found it a fine place to get some reading and writing done, besides taking in some local college scenery. While here, we had the opportunity to review some New York State’s history and, in one memorable moment for yours truly, stopped briefly in the village of Seneca Falls.

There, in 1848 a group of local women, mainly Quakers, organized an early convention here on the topic of women’s rights. Some 300 progressives attended the Seneca Falls Convention. Among those pioneering lady leaders  – feminists if you will – were Jane Hunt, whose home we visited today, Lucretia Mott and Elizabeth Cady Stanton. Approximately 40 men attended, including  Frederick Douglass, a former slave and then-editor of an abolitionist newspaper, the North Star, published in Rochester.

Which takes me back to this blog’s communication theme. We’ll be home again, in NYC, late tomorrow, and I’ve got an early class to teach on Wednesday morning.

What this means, dear readers, is that summer’s over and we’ve got to bet back to hard Medical Lessons. We’ll cover more serious stuff, for a while at least and for the most part –  journal articles, some new science and, well, learning about diseases, pathology, and how we might treat some of those.

Stay posted!

Women's History Postage Stamp

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adjusted, AM 9/8/10

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