Confusing Reports On Coffee and Cancer, and What To Do About Breakfast

When I was a medical resident in the late 1980s, we treated some patients with pancreatic cancer on a regimen nick-named the coffee protocol because it included infusions of intravenous caffeine. How absurd, we thought back then, because years earlier caffeine had been linked to pancreatic cancer as a possible cause.

Now, two new studies suggest that coffee consumption reduces a woman’s risk for developing breast cancer, according to MedPage Today:

Women who drank at least five cups of coffee daily had a significantly lower risk of postmenopausal breast cancer, an analysis of two large cohort studies suggested.

…Coffee has a paradoxical relationship with breast cancer risk. The beverage’s complex mix of caffeine and polyphenols suggests a potential to confer both carcinogenic and chemopreventive characteristics, the authors noted…

I’m incredulous, still.

As with most compounds we ingest or otherwise absorb, it’s conceivable that caffeine could damage some cells or somehow factor into some tumors’ growth just as it might suppress others, and that the dose matters. The fact is that, like most dietary chemicals, we really don’t know much about its specific effects on any cancer type.

This morning, as usual, I had an early cup of joe with low-fat milk stirred in. I might have a second cup, or a cappuccino with skim milk and cinnamon, in the afternoon. And that’s about it.

When I’m not sure if something’s good or bad for me, or both, I take it in moderation, if at all, if I choose.

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Interleukin 2, Cathy’s Planned Treatment in the Big C

I’ve been toying with the idea of messing with a cable TV show’s plotline. At the first season’s end of The Big C, the story’s protagonist decides to accept a harsh and usually ineffective treatment for her advanced melanoma: interleukin-2 (IL-2).

Laura Linney as Cathy (Showtime image, The Big C)

Cathy, played by the actress Laura Linney, understands the goal is not for a cure, but to temporize her disease for six months, when she might be eligible for a new melanoma drug through a clinical trial. Her oncologist has already completed the paperwork, according to the old script. The season ends with Cathy in a hospital bed with an IV catheter, presumably receiving the IL-2, and dreaming.

So I thought I’d explain a bit on interleukins and IL-2 in particular:

Interleukins are proteins defined by their capacity to communicate between different populations of white blood cells (between leukocytes). The term was put forth by a group of scientists who studied lymphocyte activation in a 1979 paper in the Journal of Immunology. IL-1 was the first named interleukin, IL-2 was the second, and so forth.

IL-2 was first known as Lymphocyte Activating Factor (LAF). It went by other names, too, including Helper Peak, T-Cell Replacing Factor III, and B-Cell Activating Factor (BAF). It’s a powerful cytokine, a molecule that stimulates other cells to grow and mature. Most of it comes from T-cells. For decades, doctors have been aware of IL-2’s anti-tumor potential: it can stimulate the body’s natural killer, lymphokine-activated killer (LAK) and other cytotoxic cells to destroy malignant cells.

Now, human IL-2 is available in recombinant form. This means that researchers don’t need to purify the stuff from growing cells. Instead, companies use its genetic sequence to manufacture the protein in commercial labs, much in the way that other hormones are synthesized for medicinal use – like insulin or growth hormone. Recombinant human IL-2 is called Aldesleukin and sold as Proleukin.

When I was a resident and a fellow, I gave IL-2 to some cancer patients and monitored their reactions in clinical trials. It’s not an easy drug to take, as is emphasized in The Big C, set to resume on TV June 27.

This year, on March 25, the U.S. FDA approved an antibody treatment for advanced melanoma: Ipilimumab (considered here), now sold as Yervoy. Just yesterday, as considered in the Pharma Strategy blog (with a helpful chart of BRAF inhibitors), Roche/Genentech submitted an application to the FDA for approval of an experimental agent, vemurafenib (aka PLX4032), for treatment of patients with advanced melanoma.

What will Cathy do? I have no idea. But it’s good to know her treatment options are broadening.

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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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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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Thoughts on Geraldine Ferraro, and Myeloma

Like many New Yorkers, feminists?, hematologists and other people, I was saddened to learn yesterday of Geraldine Ferraro‘s death. The Depression-era born mother, attorney, criminal prosecutor, Congresswoman, 1984 Democratic VP-candidate and part-time neighbor to yours truly, succumbed to complications of multiple myeloma at the age of 75.

Abnormal plasma cells in a bone marrow sample said to be from a patient with myeloma (Wikimedia Commons). Plasma cells have nearly-round, eccentric nuclei and abundant cytoplasm (ES).

Myeloma is a cancer of plasma cells – specialized white blood cells (mature B lymphocytes) that make antibodies. Plasma cells normally develop in the bone marrow; they can exit into the bloodstream, which is why this condition is often called a tumor of the bone marrow or, occasionally, sometimes, as a leukemia. The term myeloma comes from Greek roots – muelo (which can refer to the bone marrow) and –oma, which in medical parlance has come to stand for a tumor and may derive from soma (body).

According to the NCI, over 20,000 North Americans receive a myeloma diagnosis, and approximately 10,000 die from the disorder each year. It tends to arise in older folks, and is slightly more prevalent in men than in women. According to the SEER data, in 2007 there were over 61,000 men and women in the U.S. alive with a history of this disease.

What’s notable to me, as a hematologist, about the former congresswoman is that she lived with myeloma for over 12 years: She survived with a disease for which there were few treatments available when she was on the Presidential ticket. This was partly due to luck – always a factor in cancer outcomes, as some cases are intrinsically more aggressive than others; partly due to her access to excellent doctors and good care; and, also, likely due to advances in myeloma treatment over the past two decades.

Some perspective: When I completed my fellowship in 1993, the median survival for someone with myeloma was less than 3 years. Starting around then, most specialists steered patients under the age of 65, and in some communities, older patients as well, toward autologous stem cell transplantation – an aggressive approach that’s been shown to prolong lives of patients in randomized studies. (For the record, I’ve never been convinced by those data.) More recently, old drugs like thalidomide and its fresher derivative, lenalidomide (Revlimid), along with new drugs like bortezomib (Velcade) have demonstrated efficacy in this disease.

In my opinion, what’s ahead for doctors caring for myeloma patients – and for the patients, even more so – in this next decade, is to see if these old and new pills might be better, less costly and less toxic than transplant-based treatment regimens.

A final thought on Ferraro’s care, is that it seems she benefited from the care of experts: hematologist-oncologists, transplant physicians and other specialists and subspecialists. With all the push now for more primary care doctors – who are indeed needed – her survival with what might have been a quickly terminal illness is a testament to the value of knowledgeable, well-trained physicians who keep up with developments in an evolving field.

As for the ceiling-breaking congresswoman, my thoughts are with her family now. She was a remarkable lady in many ways.

(all links accessed 3/27/11)

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Bristol-Meyers Says Ipilimumab Prolongs Survival in Metastatic Melanoma

This morning health business mavens are chirping with bright results for ipilimumab, a monoclonal antibody that can extend life in people with metastatic melanoma. If the new data – which I haven’t seen – are true, it’s good news for patients.

In 2010, melanoma affected 68,000 people in the U.S. and led to death in approximately 8,700. The WHO estimates that over 50,000 people die of this disease worldwide annually. For patients with metastatic disease, median survival is less than one year.

Last August, investigators reported in the NEJM that ipilimumab prolonged overall survival in patients with metastatic melanoma from approximately 6 to 10 months. Those findings were based on a randomized, multicenter Phase III study funded by Bristol-Myers Squibb, the drug’s manufacturer. In that trial, the most common serious toxicity of the drug was deemed to be immune-based diarrhea. Now, the drug is up for FDA approval and Bristol-Myers is saying that another study (“024” – presumably that’s short for CA184-024) reveals prolonged survival in patients with advanced melanoma. The findings will be presented at the ASCO meeting in early June.

Ipilimumab binds a molecule called CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) on the surface of T cells. It works as a double negative kind of immune activator: by blocking CTLA-4, which normally clamps down on lymphocyte activity, the drug fosters an anti-melanoma response by the body’s healthy immune cells. Like other monoclonal antibodies, Ipilimumab is given to patients by intravenous infusion. So it’s costly in itself, and because of the need for nurses to administer the drug, IV equipment, etc.

In principle, this drug might be applied to other tumors or infectious diseases to which the immune system doesn’t adequately respond. The NIH Clinical Trials website lists other protocols, including other tumor types, for which this drug is being tried.

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When Less Chemo is Just As Good, In Treatment for Acute Myeloid Leukemia (AML)

Today’s issue of the New England Journal of Medicine includes an article with the bland title Cytarabine Dose for Acute Myeloid Leukemia. AML is an often-curable form of leukemia characterized by rapidly-growing myeloid white blood cells. Cytarabine – what we’d call “Ara-C” on rounds  – has been a mainstay of AML treatment for decades.

The new report* covers a fairly large, multicenter, randomized trial of adult patients with AML. The researchers, based in the Netherlands, Switzerland, Belgium and Germany, evaluated 860 patients who received either intermediate or high doses of Ara-C in their initial, induction chemotherapy. According to the journal, “this investigator-sponsored study did not involve any pharmaceutical companies.”

The main finding was that at a median follow-up of 5 years there were no significant differences between the groups in terms of complete remission rates, relapses or overall survival. The high-dose Ara-C offered no clear advantage in any prognostic subgroup, including those with genetic changes that bear a poor risk. Not surprisingly, Grade 3 and 4 (severe) toxicities were more common in the patients who received higher doses of Ara-C. Those patients also had lengthier hospitalizations and prolonged reduction in their blood counts.

Why am I mentioning this report, besides that it hasn’t received any press coverage? First, because the findings might matter to people who have AML and are contemplating treatment options. But mainly it’s an example of how carefully dialing down some chemotherapy doses could reduce health care costs and lessen untoward effects of cancer therapy – in terms of early toxicities and, possibly down the line, fewer secondary malignancies – without compromising long-term outcomes.

*subscription required: N Engl J Med 364: 1027-36 (2011). The free abstract includes some details on the chemo doses.

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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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The Flip Side of Unrealistic Optimism

Last week, Pauline Chen wrote on medical ethics and clinical trials. She reflects on her training at a cancer research hospital, where some cancer patients go with unrealistic optimism.

Like Dr. Chen, I spent part of my training at a famous cancer center where I worked as a resident and fellow on rotations. And yes, some patients were unreasonably optimistic and some – perhaps even most, it seemed – didn’t fully “get” the purpose of their trial, which in Phase I studies were not designed to help them. This is a real dilemma for treating oncologists.

The problem of patients’ false expectations might arise from a Lake Wobegon effect, suggests Dr. Daniel Sulmasy in the Times piece: “If you have more than 50 percent of patients saying their chances are better than average of avoiding some harm or obtaining some benefit, they are being unrealistically optimistic because you can’t say that most people are above average.”

I share Chen’s concern about ethics in clinical trials. Besides that patients don’t always (read: often) don’t understand the study, and that they may be coerced – usually subtly – into signing on, and that they may, ultimately, be simply used as objects in a researcher’s career-advancing investigation, clinical research sometimes does help humans, and progress occasionally happens in medicine. Take the woman with metastatic melanoma she recalls in the story: There might be effective drugs for her condition now, or next year.

The flip side of the Wobegon effect in medical ethics of clinical trials is that some patients (and their doctors) might have undue pessimism. These are the “50 percent” of patients who won’t show up at research centers, which could, potentially, help them to get well or at least feel better.

I think one of the biggest challenges for patients with serious conditions and their doctors is discerning what’s worth trying, and what’s snake oil in an academic outfit. Hard to know before the trial’s done –
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Learning About the Cancer Genome Atlas

A tweet from a former research colleague reminded me about the Cancer Genome Atlas, which I’d been meaning to check out. This website covers a project jointly funded by two NIH institutes: the NCI and the National Human Genome Research Institute (NHGRI). The project is about documenting cancer genetics for many, many human tumors.

Cancer Genome Atlas image

Some basics –

We all have genetic sequences we’re born with: our personal genomes. If you were to get your genome sequenced by a company, like 23andMe, they’d get some DNA from any of your cells or body fluid, and sequence your “somatic” or cellular genome. They would identify variants and mutations that you carry in the DNA of all or most of the cells in your body.

Cancer cells often contain genetic mutations that are not present in the patient’s healthy cells. So an individual’s breast cancer genome, for example, might differ from her baseline, inherited genome.

The purpose of the cancer genome project is to sequence DNA present in tumors samples so that researchers can identify specific, genetically distinct cancer forms and, eventually, develop smarter drugs that take aim at those tumor-specific mutations.

The site offers some cool, public-domain pathology and genetics images through a multimedia library. Good to know –

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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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