Talking About Physician Burnout, and Changing the System

Dear Readers,
I have a new story at the Atlantic Health. It’s on burnout among physicians. The problem is clear: Too many have a hard time finding satisfaction in the workplace. Many struggle with work-life balance and symptoms of depression.

With many difficult situations, the first step in solving a problem is in acknowledging it exists. After that, you can understand it and, hopefully, fix it. Our health care system now, as it functions in most academic medical centers and dollar-strapped hospitals, doesn’t give doctors much of a break, or slack, or “joy,” as Dr. Vineet Arora suggested in an interview. You can read about it here. The implications for patients are very real.

Glad to see that research is ongoing about physicians’ stress, fatigue and depression. Thank you to Drs. Tait Shanafelt, Mary Brandt, Vineet Arora and others for addressing these under-studied and under-discussed issues in medicine. Through this kind of work, policy makers and hospital administrators might better know how to keep doctors in the workforce, happy and healthy.

ES

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Living Like It’s Shark Week, Take 3

It’s Shark Week, or at least that’s the situation over at Discovery Channel. The annual, virtual immersion into the world of cartilaginous fish has been adopted by your author as some sort of metaphor, but she’s not sure for what.

“Live every week like it’s shark week” is a puzzle. In fact, this statement in a 30 Rock episode lurks at the periphery of Medical Lessons year-round. By now I should confess I’ve never watched an entire Shark Week program. But that doesn’t stop me from wondering about the significance.

Remotely, it’s about mental health. Science, too. I could head into a discourse on cartilage and the alleged beneficial effects for illnesses like cancer, but I don’t believe there’s any evidence to support those claims. Surely, Shark Week has to do with whether you embrace more risk or take a safe route, swim where divers go or watch TV about nature. At another level, it’s about time – a reminder that there are only so many days and nights in each week, in each month, in each year, by which we mark our lives.

So it’s about mortality. Maybe.

An alternative theory is that Shark Week is entirely devoid of deep meaning. It could be nothing more than a tool by which the Discovery Channel turns a profit in August. This year, the event was delayed until August 12. Although I’ve never taken a course in cable network programming, I would hazard a guess that this scheduling change had to do with the end of the Olympics programming that same day.

For 2012, I’ve decided to celebrate Shark Week by not watching TV. Furthermore, I won’t write on anything that has to do with breast cancer or hard science. This morning, I walked to a beach and went for a swim before breakfast. It was fantastic.

Enjoy August! And please rest up, dear readers, because I’m likely to get serious again, soon,

ES

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Another Take on Not Smoking, the Law and Tolerance

The New Yorker published a story this week, on smoking, that caught my attention. It’s by none other than F. Scott Fitzgerald. The author died in 1940 at the age of 44, after a ruinous period of addictions including alcoholism, debts and other problems.

F. Scott Fitzgerald (June, 1937), photo by Carl van Vechten

Thank You for the Light dates to 1936. The main character is a woman: “Mrs. Hanson was a pretty, somewhat faded woman of forty…” She sold girdles and craved cigarettes. Smoking had the power to “rest and relax her psychologically.” He describes her growing frustration at not being able to take a drag in offices where she did business.

The story suggests that although public and workplace smoking wasn’t illegal back then, it was frowned upon in cities like Chicago. The protagonist longs for past years and places where she could chat and share a drink or cigarette with clients after work. Times had changed, she reflects.

In Fitzgerald’s words:

…Not only was she never asked if she would like to smoke but several times her own inquiry as to whether anyone would mind was answered half apologetically with ‘It’s not that I mind, but it has a bad influence on the employees.’

This vignette offers a 1930s perspective on what some call social health – that an individual’s behavior might be influenced by neighbors’ and coworkers’ attitudes. In this story, the woman finds solace in a church. I won’t give away the ending.

The short read lingers. What’s unsettling, still, is whether the socially-driven ban on smoking helped or harmed the woman.

According to the New Yorker’s Page-Turner, the magazine rejected Fitzgerald’s story when he submitted the piece. The writer’s granddaughter recently uncovered it. This time around, it passed muster.

 

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A Closer Look at the Details on Mammography, in Between the Lines

Recently I wrote a review of Between the Lines, a helpful handbook on bio-medical statistics authored by an acquaintance and colleague, Dr. Marya Zilberberg. In that post, I mentioned my concern about some of the assumptions and statements on mammography. One thing I liked the book, abstractly, is the author’s efforts to streamline the discussion so that the reader can follow the concepts. But simplification and rounding numbers, “for ease of presentation” (p. 29) can mess up facts, significantly in ways that some primary care doctors and journalists might not appreciate. And so I offer what I hope is a clarification, or at least an extension of my colleague’s work, for purposes of helping women understand the potential benefits and risks of mammography.

In the section on mammography (pp. 28-31), the author rounds down the incidence of breast cancer in women between the ages of 40 and 50 years, from “1 in 70” (1.43%) to “1 in 100” (1%). As any marketing professional might remind us, this small change represents a 30% drop (0.43/1.43) in the rate of breast cancer in women of that age group. This difference – of 30%, or 43%, depending on how you look at it – will factor into any calculation of the false positive (FP) rate and the positive predictive value (PPV) of the test.

For women ages 40-49 Have breast cancer Don’t have breast cancer
If estimate 1 in 100, 1.0 % 100 9,900
If estimate 1 in 70, 1.43 % 143 9,857

Keep in mind that these same, proportional difference would apply to any BC screening considerations – in terms of the number of women affected, the potential benefits and costs, for the 22,996,493 women between the ages of 40 and 49 counted in the 2010 U.S. Census,

My colleague estimates, fairly for this younger age group of women (who are relatively disposed to fast-growing tumors), that the screening technology (mammography) only picks up 80% of cases; 20% go undetected. In other words – the test is 80% sensitive; the false negative, FN, rate is 20%. In this same section, she considers that the FP rate as 10%. Let’s accept this (unacceptably high) FP rate for now, for the sake of discussion.

As considered in Between the Lines:

If FP rate is 10%, prevalence 1 in 100 Really have BC Don’t have BC Total
Mammography + 80 990 1,070
Mammography – 20 8,910 8,930
Total 100 9,900 10,000

But the above numbers aren’t valid, because the disease affects over 1 in 70 women in this age bracket. Here’s the same table with a prevalence of 1 in 70 women with BC:

If FP rate is 10%, prevalence 1 in 70 Really have BC Don’t have BC Total
Mammography + 114 986 1,100
Mammography – 29 8,871 8,900
Total 143 9,857 10,000

In this closer approximation to reality, the number of true positives is 114, and false positives 986, among 1,100 abnormal screening results. Now, the PPV of an abnormal mammogram is 114/ (114+986) = 10.4%. So the main statistical point – apart from the particulars of this discussion –  is that a seemingly slight rounding down can have a big impact on a test’s calculated and perceived value. By adjusting the BC rate to its prevalence of approximately 1 in 70 women between 40 and 49 years, we’ve raised the PPV from 7.5% to 10.4%.

Here I must admit that I, too, have rounded, although I did so conservatively very slightly. I adopted a 1 in 70 approximation (1.43%) instead of 1 in 69 (1.45%), as indicated on the NCI website. If we repeat the table and figures using a 1 in 69 or 1.45% prevalence rate and 6% FPS, the PPV rises a tad, to 10.5%.

Now, we might insert a different perspective: What if the false positive rate were 6%, as has been observed among sub-specialist radiologists who work mainly in breast cancer screening?

If FP rate is 6%, prevalence 1 in 70 Really have BC Don’t have BC Total
Mammography + 114 591 705
Mammography – 29 9266 9,295
Total 143 9,857 10,000

As you can see, if we use a FP rate of 6% in our calculations, the total number of FPs drops to 591 among 10,000 women screened. In this better-case scenario, the PPV of the test would = 114/ (114+591) =16%. Still, that’s not great – and I’d argue that public health officials, insurers and patients should be pushing for FP rates closer to 2 or 3% – but that’s irrelevant to my colleague’s point and her generally instructive work.

My second concern has to do with language, and making the consequences of false positives seem worse than they really are. On page 29, the author writes: “ So, going back to the 10,000 women being screened, of 9,900 who do NOT have cancer… 10%, or 990 individuals will still be diagnosed as having cancer.” The fact is, the overwhelming majority of women with positive mammograms won’t receive a cancer diagnosis. Rather, they’ll be told they have “an abnormal result, or a finding that suggests the possibility of cancer and needs further evaluation,” or something along those lines. It would be unusual in practice to jump from a positive mammogram straight to a breast cancer diagnosis. There are steps between, and every patient and journalist should be aware of those.


Finally, if I were to write what I really think, apart from and beyond Between the Lines – I’d suggest the FP rate should be no higher than 2 or 3% in 2012. This is entirely feasible using extant technology, if we were to change just two aspects of mammography practice in the U.S. First, require that all mammograms be performed by breast radiologists who get extra training and focus in their daily work almost exclusively on breast imaging. Second, make sonograms – which, together with mammograms, enhance the specificity of BC screening in women with dense breasts– universally available to supplement the radiologists’ evaluations of abnormal mammograms and dense breasts in younger women.

By implementing these two changes, essentially supporting the practice of sub-specialists in breast radiology, we could significantly lower the FP rate in breast cancer screening. The “costs” of those remaining FPs could be minimized by judicious use of sonograms, needle biopsies and other measures to reduce unnecessary surgery and over-treatment. Over the long haul, we need to educate doctors not to over-treat early stage disease, but that goes far beyond this post and any one woman’s analysis of mammography’s effectiveness.

All for now,
ES

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What Does a Bikini Parade Have to Do with Breast Cancer?

A recurring question on this blog is this: Is there a limit, in terms of appropriateness or “correctness,” in fundraising for causes that would help put an end to breast cancer?

My blogging colleague and friend, fellow BC ~survivor/advocate/NBCC summit attendee and former chemo recipient, AnneMarie Ciccarella, @chemobrainfog wrote about an upcoming bikini parade planned by a tanning salon owner in Madison Lake, MN. Proceeds from the march will go toward a nonprofit group called the Breast Cancer Natural Prevention Foundation (preventbc.org). This true story is problematic at many levels, as AnneMarie points out.

But sometimes an extreme case of something – here what’s billed as a BC fundraiser – can be instructive. A few months ago I wrote about Boobstagram – a French website that asks women to submit pictures of their breasts to increase awareness of the value of healthy breasts. The site, vaguely and with few words, tries connecting the barely clad images with “the fight against cancer.” Although I’m still not convinced that the concept utterly lacks merit in principle, and maintain that some of the voices raised here were, perhaps, too quickly dismissive and uptight about the possibility of fundraising or BC activism by this method, I acknowledge that the men running that company seem to be doing nothing useful in terms of reducing breast cancer or its complications.

The Minnesota bikini march will take place on July 28. The line-up starts at noon. The walk will begin at 1PM. According to the announcement on the Electric Beach Mankato website, “only females in bikinis will be counted toward the world record.” The organizer and salon owner, Cynthia Frederick, needs 451 participants to break the Guinness World Records mark for largest bikini parade. That site lists the record as 357 women, based on a 2011 event in Queensland, Australia. But that achievement was recently surpassed in Panama City, FL. What’s different about the prior demonstrations is that there was no pretense of raising money or awareness to help fight, prevent or cure breast cancer.

Minnesota bikini parade participants will pay $20 or $25 for tee shirts. Net proceeds will to go the Breast Cancer Natural Prevention Foundation. The foundation’s site suggests that sunlight prevents BC by increasing vitamin D levels (which is total BS, to be perfectly clear). Taking too much vitamin D can do damage, as can excessive sun exposure.

As I read this, a tanning salon – a business that causes melanoma and other skin cancers – is promoting a walk of bikini-wearing women in midday summer sun to break an amusing world’s record. The parade will, if anything, harm those women who, naively or otherwise, believe they’re supporting a legitimate effort to prevent breast cancer. Any funds raised will support a foundation that promotes what’s tantamount to snake oil for the disease.

So there is a line, in the sand… And it’s been crossed!

If I were an investigative journalist, I’d want to know more about the organization that calls itself the “Breast Cancer Natural Prevention Foundation.” Does it get tax breaks? If so, why?

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Three Reasons to Celebrate the Supreme Court’s Decision on Obamacare

I’m thrilled about today’s SCOTUS decision. The Supreme Court upheld the gist of the Affordable Care Act (ACA). Am I surprised? Yes, like pretty much everyone – I didn’t anticipate Chief Justice Roberts’ clever argument about the individual mandate.

What I see in this is first, a win for patients, who now are more likely to get health care if and when they need it – preventive and otherwise. L’Chaim!

Second, it’s a win for the Obama administration and the Democrats. And although I went to journalism school at Columbia University and was told that “real journalists don’t share their opinions,” I do: I’m a registered, reliable, primary-voting Democrat. The ACA is, so far, President Obama’s signature achievement. This SCOTUS decision supports the President’s goal of simultaneously reining in health care costs and expanding coverage to all. It raises the likelihood of President Obama’s re-election. Cheers!

Finally, and at a deeper level, the decision reflects the power of one man’s thoughtfulness to change the outcome of a seemingly bleak situation. (This can happen in oncology and other kinds of medicine, when most of the doctors or specialists on a case throw up their hands or say “it’s impossible because of blah, blah, blah,” and they might refer to some old published studies on old drugs, or something like that.) What Chief Justice Roberts did was think out-of-the box, carefully and within a legal framework. Like a good, smart doctor, morally grounded and, perhaps, influenced by compassion (hard to tell), the Chief Justice figured out a legally acceptable way for his court to do the right thing. By his wisdom, he will have saved more than a few lives. Bravo!

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How Much Do You Want Your Doctors To Say About Risks of Treatment?

When I was diagnosed with breast cancer, I was working as a board-certified oncologist. The initial decisions most patients face – which doctor to see, what kind of doctor to see, and at which medical center to see them – were basically non-decisions. I knew, within an instant of my diagnosis, who I’d ask to be my oncologist, surgeon and plastic surgeon. Those choices were straightforward, because I knew what those physicians were like in terms of how they cared for patients, their knowledge and other aspects of their practices and personalities.

The harder decisions were what treatment to take, or not, for my early-stage breast cancer. I was perhaps the most informed cancer patient who could walk into an oncologist’s office. I was familiar with the different regimens. I knew that adjuvant chemotherapy would, roughly and over the long haul, reduce my odds of recurrence by a third. I was aware that, if I opted for a lumpectomy, radiation treatment would reduce the local recurrence rate but was unlikely to affect my long-term survival. I understood that dose-intense regimens were more likely to make me sick and more likely to cause problems down the road.

And yes, in the back of my head I knew that chemotherapy can cause another cancer. Did I think about that possibility? The best answer is, probably, not so much. I was coping with the present.

But that knowledge did influence the decision I made to take a relatively “light” dose of chemotherapy. I was lucky, also, in that I understood my pathology. My tumor, at 1.5 cm, with a negative sentinel node and generous expression of hormone receptors, was a good-prognosis tumor. I was 42 years old, and wanted to live for a few more decades if I survived my spine surgery (another story). I chose the minimal amount of chemo that had been shown in clinical trials to reduce the odds of recurrence.

Last week, I wrote a piece for the Atlantic on how doctors and patients talk about the risks of chemotherapy, or not, and whether patients listen or necessarily want to listen. The reason I put it out there is because I’ve seen doctors shy away from this part of the conversation about cancer treatment. I’m a firm believer in informed consent, and in patients’ access to as much information as they choose to have. If you get chemotherapy, you have the right to know about these risks, and to ask your doctor about them.

I’ve been there with patients who’ve said: “please, don’t tell me this. I can’t deal with it.” Some might even consider it cruel to tell patients with a serious, urgent and treatment-needing condition details of all the possible side effects. Many ask, “what would you do, doctor, if it were someone in your family?” And if they like and respect you, they go with your recommendation.

This kind of paternalism, when a doctor assesses the risks and benefits, and spares the patient’s “knowing” seems anachronistic. But it may, still, be what many people are looking for when and if they get a serious illness. Not everyone wants a “tell me everything” kind of physician. What do you think?

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

Dear Readers,

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

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

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

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

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

ES

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FDA Approves Pertuzumab for Advanced, Her2+ Breast Cancer

We’re on a roll for new treatments of the Her2+ form of breast cancer. On Friday the FDA approved Pertuzumab, a monoclonal antibody, for advanced cases. As indicated, the drug would be given along with another monoclonal antibody, trastuzumab (Herceptin) and a chemotherapy, docetaxel (Taxotere) to patients with advanced breast tumors with high levels of Her2.

The new treatment’s brand name is Perjeta. Like Herceptin, this reagent works by attaching to the Her2 receptor on a cancer cell’s surface. But it differs by binding a distinct part of the molecule; its mechanism of action is said to complement that of Herceptin.  You might recall that HER protein family members are complex signaling molecules that span cell membranes. Her1 is the Epidermal Growth Factor Receptor; it’s turned on when bound by its partner, or molecular ligand, Epidermal Growth Factor(EGF). The others are Her2, -3 and -4.

EGFR (Her1) signaling, Wiki-Books image

The science behind drugs that interfere with Her2 receptors and signaling is nicely summarized in a recent, open-access Nature Reviews Clinical Oncology article. Herceptin binds a particular segment of Her2 on the outside of the cell; this leads to failed signaling on the inside, including cell division signals, and causes cell death by several mechanisms. Pertuzumab binds a distinct segment of Her2 in such a way that it can’t form a complex with the related Her3 molecule; this interaction is needed for Her2 to stimulate cell growth.

The FDA’s approval rests largely on results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study, published earlier this year in the NEJM. In that Phase III study, just over 800 patients were randomly assigned to receive a standard regiment – Herceptin in combination with Taxotere plus a placebo infusion, or the Herceptin-Taxotere combination plus Pertuzumab.

The patients who received Pertuzumab did better in terms of Progression Free Survival (PFS, 18.5 months vs. 12.4 months; this difference holds strong statistical merit). There is a trend, also, in terms of Overall Survival: at a median follow-up point of 19.3 months, there were more deaths in the placebo group. But a statistically significant difference was not reached. Toxicity was reported as “generally similar” in the two groups, but there was more diarrhea, dry skin and rashes among those who got Pertuzumab (Table 3). Heart problems, a known toxicity of the Herceptin-Taxotere regimen, were slightly less common with Pertuzumab. Hair loss, presumably from the chemotherapy part of the regimen, was common in both groups.

One curious thing I noticed, in re-reading the January report, is that although the median age for both patient groups was 54 years, the control patients ranged from 27 – 89 in age; those who got Pertuzumab ranged from 22 – 82 years. Although the younger “shift” of Pertuzumab-receiving patients relative to the controls is unlikely to affect the PFS, it’s odd to include an 89 year old patient on an experimental protocol involving infusions of two monoclonal antibodies along with chemo.

This is a super-costly regimen. Like Herceptin, and like the experimental compound antibody, DM1, about which I wrote last week, Perjeta is manufactured by Genentech. As detailed by Andrew Pollack in the NY Times: the wholesale price for Perjeta will be $5,900 per month for a typical woman; Herceptin costs $4,500 per month. So we’re talking about a treatment in which the monoclonal antibodies alone cost over $10K per month. “A typical 18-month course of treatment would be more than $187,000,” he indicated. But if you add on the costs of the Taxotere, drugs like Benadryl and Decadron to minimize allergic reactions, anti-nausea meds, charges for the infusion and monitoring…It’ll be a lot more than that.

As the FDA notes in its press release, production of Perjeta is currently limited due to a technical issue at the Genentech manufacturing plant. Meanwhile, investigators, doctors and patients will have to sort out the relative value of this drug, on top of the others – including pills – for Her2+ disease.

My opinion is not quite formed on this new antibody. The FDA’s decision was based on results from one trial of 808 patients, half of whom didn’t get the experimental drug. Accrual began in 2008; its broad clinical effects, and long-term toxicities, can’t be established yet. It may be, ten years from now, that Perjeta will be used routinely in patients with other, Her2+ kinds of cancer. Or it may be a toxic bust.  How (and if) we’ll test and compare different doses of Perjeta and potential combinations with other drugs, small pills and traditional chemotherapies – which are many – is not clear. You could, for example, combine one or both of the antibodies with a drug like Lapatinib (Tykerb), that inhibits Her2-triggered growth signals inside the cell.

The problem is that oncologists, and facilities including academic centers where revenue is generated by giving drugs by infusion, now have a huge financial incentive to give the Herceptin-Perjeta-Taxotere regimen. This regimen is approved for first-line treatment of metastatic, Her2+ breast cancer; you don’t have to have “failed” another regimen, as was required for the EMILIA trial. As I understand this approval, an oncologist seeing a woman with recurrent or metastatic Her2+ breast cancer could, immediately, prescribe the 3-drug combination.

It’s impressive that the CLEOPATRA folks included an 89 year old patient in the study. But at some point, you have to wonder where we might draw lines. I’ve no answers on that.

All for now, maybe for the week,

ES

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Sad News, from the Metastatic Breast Cancer Network

Dear Readers,

I was saddened today to learn of the death of Suzanne Herbert. Last October, I met Suzanne at a conference. She seemed familiar; that was because I’d read about her life with metastatic breast cancer (MBC) a few months back in the New York Times. Like some women I’ve known w/ MBC, Suzanne didn’t appear sick. At least not then. She seemed positive, and thoughtful. Energetic, even.

According to the Metastatic Breast Cancer Network, Suzanne lived with metastatic disease for over 7 years. She died last week at age 47.

– ES

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

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

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

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

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

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

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

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

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

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

My main, initial concerns are two:

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

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

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

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

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

All for now,

ES

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The NBCC Holds Annual Summit and Pushes for Deadline 2020

Last week the National Breast Cancer Coalition (NBCC) held its annual summit. The meeting drew over 600 women to its opening rally in a Crystal City ballroom on Saturday, along with students who participated in sessions for Emerging Leaders, and a few men who joined in lectures and panels, and lobbied on Tuesday on Capitol Hill.

The NBCC aims to get HR 3067, the Accelerating the End of Breast Cancer Act, passed by the House of Representatives and, ultimately, into law. The bill ties in with Deadline 2020 and with the conference theme: “It’s Time.”

The opening rally, organized in the style of a political convention, was lively. When I entered, participants – or “activists,” as they might be called – were rocking to Three Dog Night’s Joy to the World. Attendees congregated by state and region. Most wore festive garments and signs over black tee shirts carrying the Deadline logo: women from Maine wore floppy red lobster hats; a contingent from Pennsylvania held brightly-decorated kite-posters; a group from Oregon played kazoos (to We’re Not Gonna Take It) and supported multicolored umbrellas over their heads; members of the CBCC lifted Rosie the Riveter boards proclaiming: “We Can Do It!” Each region offered a progress report. In videos, these demonstrated a mix of activism (“waving breast cancer goodbye” on a Rhode Island beach) and seriousness (scientist in a lab, explaining why the research matters).

Fun aside – the meeting’s mood was overwhelmingly serious. Each day’s session opened with a moment of silence to recall women who have died from breast cancer. There were plenary lectures, and smaller educational meetings on topics like “A Critical Review of New Therapies for Metastatic Breast Cancer,” “Estrogen Exposure throughout the Life Cycle,” “Nuts and Bolts of Congress,” “and “The Environment and Breast Cancer.” Many of the women there have metastatic cancer, or had cancer. I had lunch one day with a woman whose early-stage cancer came back after 15 years. Many of the college-age people attending have moms with advanced disease or who died from that. There were young people who’d had breast cancer – some under 30 years old. The few men I spoke with were affected by their wives and mothers’ illnesses. You couldn’t walk a few feet without hearing a sad tale, or seeing the outcome of loss, in motivating people to take action.

In her remarks, Fran Visco, the NBCC Founder and leader, reminded the group that breast cancer remains a leading cause of cancer deaths. Each day, on average, 110 women die in the U.S. from breast cancer. That’s the equivalent of a woman dying every 14 minutes from the disease, she explained. “This should not be considered success, or even meaningful progress.”

“We need to take a less comfortable approach,” she said. “The system rewards safe ideas. We need to take risks.” She spoke of the Artemis project, an NBCC-supported research program to develop a preventive breast cancer vaccine. “There’s a moral imperative to do these trials,” she said. “We’ll get scientists to form new collaborations, to change their focus not on the next grant, or publication, but on the real goal, which is saving patients’ lives.”

In the 20 years since NBCC was founded there’s been progress, she said. “But we’re nowhere near close enough.” She referred to Dr. Jonas Salk, whose polio vaccine came through after just seven years in the lab, and – as did others at the same meeting – to JFK’s 1961 promise to put a man on the moon. That seemingly impossible mission got done in less than nine years. The idea of the Accelerating the End of Breast Cancer Act is to leverage our nation’s prior investment in biotechnology, and to use that work – including much research already done – to end to breast cancer and stop metastases. Visco hopes to deliver a petition to the President on inauguration day in January, 2013.

Through the meeting, I gained a better sense of the organization and Deadline’s purpose. In the words of Senator Kirsten Gillebrand, who met with a delegation from New York on Tuesday: “It creates an urgency about the issue.”

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10 Newly-Defined Molecular Types of Breast Cancer in Nature, and a Dream

Breast cancer is not one disease. We’ve understood this for decades. Still, and with few exceptions, knowledge of BC genetics – information on tumor-driving DNA mutations within the malignant cells – has been lacking. Most patients today get essentially primitive treatments like surgical hacking, or carving, traditional chemotherapy and radiation. Some doctors consider hormone therapy as targeted, and thereby modern and less toxic. I don’t.

Until there’s a way to prevent BC, we need better ways to treat it. Which is why, upon reading the new paper in Nature on genetic patterns in breast cancer, I stayed up late, genuinely excited. As in thrilled, optimistic..The research defined 10 molecular BC subgroups. The distinct mutations and gene expression patterns confirm and suggest new targets for future, better therapy.

The work is an exquisite application of science in medicine. Nature lists 31 individuals and one multinational research group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), as authors. The two correspondents, Drs. Carlos Caldas and Samuel Aparicio, are based at the University of Cambridge, in England, and the University of British Columbia in Vancouver, Canada. Given the vastness of the supporting data, such a roster seems appropriate, needed. The paper, strangely and for all its worth, didn’t get much press –

Just to keep this in perspective – we’re talking about human breast cancer. No mice.

The researchers examined nearly 2000 BC specimens for genetic aberrations, in 2 parts. First, they looked at inherited and acquired mutations in DNA extracted from tumors and, when available, from nearby, normal cells, in 997 cancer specimens – the “discovery set.” They checked to see how the genetic changes (SNPs, CNAs and/or CNVs) correlated with gene expression “landscapes” by probing for nearly 29,000 RNAs. They found that both inherited and acquired mutations can influence BC gene expression. Some effects of “driver” mutations take place on distant chromosomal elements, in what’s called a trans effect; others happen nearby (cis).

Next, they honed in on 45 regions of DNA associated with outlying gene expression. This led the investigators to discover putative cancer-causing mutations (accessible in supplementary Tables 22-24, available here). The list includes genes that someone like me, who’s been out of the research field for 10 years, might recall – PTEN, MYC, CDK3 and -4, and others. They discovered that 3 genes, PPP2R2A, MTAP and MAP2K4 are deleted in some BC cases and may be causative. In particular, they suggest that loss of PPP2R2A may contribute to luminal B breast cancer pathology. They find deletion of MAP2K4 in ER positive tumors, indicative of a possible tumor suppressor function for this gene in BC.

Curtis, et al. in "Nature": April 2012

The investigators looked for genetic “hotspots.” They show these in Manhattan plots, among other cool graphs and hard figures, on abnormal gene copy numbers (CNAs) linked to big changes in gene expression. Of interest to tumor immunologists (and everyone else, surely!), they located two regions in the T-cell receptor genes that might relate to immune responses in BC. They delineated a part of chromosome 5, where deletions in basal-like tumors marked for changes in cell cycle, DNA repair and cell death-related genes. And more –

Cluster Analysis (abstracted), Wikipedia

Heading toward the clinic, almost there…

They performed integrative cluster analyses and defined 10 distinct molecular BC subtypes. The new categories of the disease, memorably labeled “IntClust 1-10,” cross older pathology classifications (open-access: Supplementary Figure 31) and, it turns out, offer prognostic information based on long-term Kaplan-Meier analyses (Figure 5A in the paper: Supplementary Fig 34 and 35). Of note, here, and a bit scary for readers like me, is identification of an ER-positive group, “IntClust 2” with 11q13/14 mutations. This BC genotype appears to carry a much lesser prognosis than most ER-positive cases.

Finally, in what’s tantamount to a 2nd report, the researchers probed a “validation set” of 995 additional BC specimens. In a partially-shortened method, they checked to see if the same 10 molecular subtypes would emerge upon a clustering analysis of paired DNA mutations with expression profiles. What’s more, the prognostic (survival) information held up in the confirmatory evaluation. Based on the mutations and gene expression patterns in each subgroup, there are implications for therapy. Wow!

I won’t review the features of each type here for several reasons. These are preliminary findings, in the sense that it’s a new report, albeit a model of what’s a non-incremental published set of observations and analysis; it’s early for patients – but not for investigators – to act on these findings. (Hopefully, this will not be the case in 2015, or sooner, preferably, for testing some pertinent drugs in at least a subset of the subgroups identified.) Also, some of the methods these authors used came out in the past decade, after I stopped doing research. It would be hard for most doctors to fully appreciate the nuances, strengths and weaknesses of the study.

Most readers can’t know how skeptical I was in the 1990s, when grant reviewers at the NCI seemed to believe that genetic info would be the cure-all for most and possibly all cancers. I don’t think that’s true, nor due most people involved with the Human Genome Project, anymore. The Cancer Genome Atlas and Project should help in this regard, but they’re young projects, larger in scope than this work, and don’t necessarily integrate DNA changes with gene expression as do the investigators in this report. What’s clear, now, is that some cancers do respond, dramatically, to drugs that target specific mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated now with pills, often with terrific responses.

Last night I wondered if, in a few years, some breast cancers might be treated without surgery. If we could do a biopsy, check for the molecular subtype, and give patients the right BC tablets. Maybe we’d just give just a tad of chemo, later, to “mop up” any few remaining or residual or resistant cells. The primary chemotherapy might be a cocktail of drugs, by mouth. It might be like treating hepatitis C, or tuberculosis or AIDS. (Not that any of those are so easy.) But there’d be no lost breasts, no reconstruction, no lymphedema. Can you imagine?

Even if just 1 or 2 of these investigators’ subgroups pans out and leads to effective, Gleevec-like drugs for breast cancer, that would be a dream. This can’t happen soon enough.

With innovative trial strategies like I-SPY, it’s possible that for patients with particular molecular subgroups could be directed to trials of small drugs targeting some of the pathways implicated already. The pace of clinical trials has been impossibly slow in this disease. We (and by this I mean pharmaceutical companies, and oncologists who run clinical trials, and maybe some of the BC agencies with funds to spend) should be thinking fast, way ahead of this post –

And given that this is a blog, and not an ordinary medical publication or newspaper, I might say this: thank you, authors, for your work.

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The Outlier’s Message, and Evolutionary Science in Breast Cancer

This past week I read several attitude-altering articles about breast cancer.

Kathy Rich, as featured in ‘O’ Magazine

The first lesson, if I might call it that – in the way an oncologist can learn from variations in her patients’ pathology and clinical outcomes – comes from the case of Katherine Russell Rich, who died last week at the age of 56. As reported by Katherine O’Brien in the I Hate Breast Cancer Blog, Rich lived with metastatic BC (MBC) for 18 years. That’s phenomenal, was my first reaction to this news. The prognosis for MBC is said to be around 3 years, and Rich lived for 18 years beyond her tumor’s recurrence with stage IV disease.

As sad and unsatisfactory as this outcome may seem, and it is, Rich’s story offers hope for life beyond the 3 or 4 or 5 years some women with MBC pray, “ask” or otherwise bargain for, fingers-crossed…

As she detailed in an O article, Rich’s initial diagnosis came when she was 32 years old, in 1988. The Times, in an obituary, tells of her lumpectomy, chemo and radiation. In 1993 her cancer came back in bones including her spine. She had a bone marrow transplant, but the disease progressed. Ultimately, she coursed through various and some archaic hormone treatments.

Along the way, she lost or quit a job in publishing, or both, and traveled to India, and authored two books. In a 2010 first-person story about her case, she told of updating her status – of being alive – at Breastcancer.org each year. She wrote:

…I tell the women how deeply I believe there’s no such thing as false hope: all hope is valid, even for people like us, even when hope would no longer appear to be sensible.

Life itself isn’t sensible, I say. No one can say with ultimate authority what will happen — with cancer, with a job that appears shaky, with all reversed fortunes — so you may as well seize all glimmers that appear.

My take, as an oncologist and former clinician, is that patients sometimes surprise you. Hard to know which woman will respond to a non-targeted treatment, or even a drug like an estrogen modulator, without trying. And I wonder – and this is speculative, but maybe, likely, the two together – doctor and patient – worked together to see what worked in Rich’s case over nearly 2 decades, and what didn’t work.

A Bell Curve

If a drug helps, keep it going; if it hurts, stop. There are so many algorithms in medicine, and molecular tools, but maybe the bottom line is how the, one, your patient is doing.

Which leads me to another post, by Dr. David Gorski, a breast cancer surgeon and researcher who blogs as Orac – what once was imagined as a fabulously capable information processor, at Respectful Insolence. He describes how tough it can be to define, and thereby target or destroy, any individual patient’s breast tumor because the cancer cells are constantly changing. Within each woman’s tumor, an evolution-like process is ongoing, leading to selection of treatment-resistant cells. This is not news in oncology; the concept has been understood for years as it applies to “liquid” tumors like leukemia, as he points out.

In breast cancer, understanding the complexity of each case is more recent. Gorski considers a genetic analysis of 104 triple negative breast cancer (TNBC) cases presented at the recent AACR meeting and published last week in Nature:

“…The 59 scientists involved in this study expected to see similar gene profiles when they mapped on computer the genomes of 100 tumours.

But to their amazement they found no two genomes were similar, never mind the same. “Seeing these tumours at a molecular level has taught us we’re dealing with a continuum of different types of breast cancer here, not just one,” explains Steven Jones, co-author of this study.

…TNBC is not a single disease. In fact, even an individual TNBC tumor is not a single disease. Tumor cells evolve as they proliferate, so that the cells in them are genetically heterogeneous. The cells growing in one area of a tumor can and often do harbor markedly different genetic mutations from the cells growing in another part of the tumor…

The team found that each tumor displayed multiple “clonal genotypes,” suggesting that the cancer would have to be treated as multiple diseases, rather than a single entity.

So besides that there are distinct subtypes of breast cancer, those labeled as TNBC are diverse and contain variation within; each patient harbors sub-clones of malignant cells that, in principle, respond differently to treatment.

Orac, the fictional supercomputer (Wiki-Commons image)

Putting these links together –

The message from Katherine O’Brien, who lives with MBC and blogs about it, is that one outlier – like Katherine Russell Rich – can provide hope to other patients and, maybe, clues for scientists about why she lived for so long with metastatic BC. The message from Orac, a physician-scientist blogger, is how hard it is to pinpoint an individual breast tumor’s molecular aspects, because the disease is so mutable and diverse.

The problem, and this reflects evolution in my thinking over a long while, is that published data – the gold standard, what supports EBM – are largely limited to findings based on trials of groups. We understand now, better than we did 10 or 20 years ago, that each patient’s tumor is unique and can evolve over time, naturally or in response to therapy. Clinical trials, though rigorously planned and elaborately structured, are incredibly expensive and flip-floppy, disappointing overall.

What I’m thinking –

Algorithms – except in the broadest sense – may not offer the optimal approach to cancer treatment. Maybe the median doesn’t matter so much as we’d thought.

Here’s a ~retro idea: In 2012, maybe the ideal and most cost-effective oncology practice would blend low-tech observations – like findings on physical examination and how the patient’s feeling – with occasional, high-tech analyses – like markers for genetic drift within a tumor. If doctors are well-trained and non-robotic, in either the literal or figurative sense, and if they lack COIs regarding treatment decisions, they’d provide better, more effective and personalized treatments than what’s typically offered based on evidence reached through elaborate, costly clinical trials of many patients with similar but non-identical cancers.

All for now,

ES

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

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

Here are a few of my concerns:

1. None of the four authors is an oncologist.

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

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

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

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

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

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

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

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

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

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

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

A dangerous message, IMO.

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

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Why I Support Health Care Reform

One advantage of blogging is that I can share my ideas, directly, with people who find them interesting, provocative or otherwise read-worthy. So for those who are curious, here is my general view on health care reform (HCR) by any name, in 3 points:

First, we need it. The U.S. health care system doesn’t work. It doesn’t serve doctors. Good physicians are few and far between in some geographical regions, in primary care and in needed specialties (like oncology and geriatrics). It doesn’t serve people who might be patients, except if they happen to work for a generous employer that offers a good plan (few do), they are rich enough so they might spend thousands each year out-of-pocket and out-of-network, or they are most fortunate of all, having no serious medical problems to contend with or pay for.

Second, although I wholeheartedly support the Affordable Care Act, because it’s a step in the right direction, I don’t think the legislation goes far enough. We need a simpler, single-payer solution, as in a national health care program, Medicare-style, for all. Why? Because the quasi-plan for state-based exchanges, each with competing offerings and not necessarily interpretable terms of coverage, is too complicated. There’s no reason to think a free market operating at the state level would match the public’s or many individuals’ medical needs. As long as each provider is trying to make a buck, or a billion, it won’t put patients’ access to good care first. Besides, there’ll be administrative costs embedded in each exchange that we could live better without. As for private insurers, well, I couldn’t care less about the well-being of those companies or their executives’ incomes.

Profit is not what medical care is about, or should be about. What we need is a simple, national health plan, Europe-style, available to everyone, with minimal paperwork and, yes, limits to care.

Third point – on rationing.

Some of my readers may wonder how I, who support some costly components of good medical care, like providing breast cancer screening for middle-aged women and sometimes giving expensive drugs to people with illness, favor health care reform. New cancer meds cost around $100,000 year, more or less, as do innovative treatments for cystic fibrosis, inflammatory bowel disease, rheumatoid arthritis and other conditions. I don’t think the sane solution is abandoning expensive but life-saving and quality-of-life-improving treatments.

The hardest part of this debate and what’s so rarely discussed is the appropriate limits of medical treatment, not based on costs – which we can certainly afford if we pull back on administrative expenses of health care and insurers’ huge profits – but on factors like prognosis and age. So, for example, maybe a 45 year old man should get a liver transplant ahead of an 80 year old man. Screening for breast cancer, if it is valuable as I think it is, should perhaps be limited to younger women, maybe those less than 70 or 75, based on the potential for life-years saved. Maybe we shouldn’t assign ICU beds to individuals who are over 85, or 95, or 100 years old.

The real issue in HCR, if you ask me, is who would decide on these kinds of questions. That conversation’s barely begun, and I would like to participate in that…

Meanwhile, the Supreme Court is busy doing its thing, sorting out whether the Affordable Care Act is constitutional or not. I’m glad they’re on the case, so that they might find that it stands and we can move on and forward.

#Obamacare is right –

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What Does it Mean if Primary Care Doctors Get the Answers Wrong About Screening Stats?

Last week the Annals of Internal Medicine published a new report on how doctors (don’t) understand cancer screening stats. This unusual paper reveals that some primary care physicians – a majority of those who completed a survey – don’t really get the numbers on cancer incidence, 5-year survival and mortality.

An accompanying editorial by Dr. Virginia Moyer, a Professor of Pediatrics and current Chair of the USPSTF, drives two messages in her title, What We Don’t Know Can Hurt Our Patients: Physician Innumeracy and Overuse of Screening Tests. Dr. Moyer is right, to a point. Because if doctors who counsel patients on screening don’t know what they’re speaking of, they may provide misinformation and cause harm. But she overstates the study’s implications by emphasizing the “overuse of screening tests.”

The report shows, plainly and painfully, that too many doctors are confused and even ignorant of some statistical concepts. Nothing more, nothing less. The new findings have no bearing on whether or not cancer screening is cost-effective or life-saving.

What the study does suggest is that med school math requirements should be upped and rigorous, counter to the trend. And that we should do a better job educating students and reminding doctors about relevant concepts including lead-time bias, overdiagnosis and – as highlighted in two valuable blogs just yesterday, NPR Shots and Reporting on Health Antidote – the Number Needed to Treat, or NNT.

The Annals paper has yielded at least two unfortunate outcomes. One, which there’s no way to get around, is the clear admission of doctors’ confusion. In the long term, this may be a good thing, like admitting a medical error and then having QA improve as a consequence. But meanwhile some doctors at their office desks and lecterns don’t realize what they don’t know, and there’s no clear remedy in sight.

Dr. Moyer, in her editorial, writes that medical journal editors should carefully monitor reports to ensure that results aren’t likely misinterpreted. She says, in just one half-sentence, that medical educators should improve teaching on this topic. And then she directs the task of stats-ed to media and journalists, who, she advises, might follow the lead of the “watchdog” HealthNewsReview. I don’t see that as a solution, although I agree that journalists should know as much as possible about statistics and limits of data about which they report.

The main problem elucidated in this article is a failure in medical education. The cat’s out of the bag now. The WSJ Heath Blog covered the story. Most doctors are baffled, says Fox News. On its home page, the Dartmouth Institute for Health Policy & Clinical Practice links to a Reuters article that’s landed on the NIH/NLM-sponsored MedlinePlus (accessed 3/15/12). This embarrassment  further compromises individuals’ confidence in doctors they would and sometimes need rely on.

We lie, we cheat, we steal, we are confused… What else can doctors do wrong?

The second, and I think unnecessary, problematic outcome of this report is that it’s been used to argue against cancer screening. In the editorial Dr. Moyer indulges an ill-supported statement:

…several analyses have demonstrated that the vast majority of women with screen-detected breast cancer have not had their lives saved by screening, but rather have been diagnosed early with no change in outcome or have been overdiagnosed.

The problem of overdiagnosis, which comes up a lot in the paper, is over-emphasized, at least as it relates to breast cancer, colon cancer and some other tumors. I  have never seen a case of vanishing invasive breast cancer. In younger women, low-grade invasive tumors are relatively rare. So overdiagnosis isn’t applicable in BC, at least for women who are not elderly.

In the second paragraph Dr. Moyer outlines, in an unusual mode for the Annals, a cabal-like screening lobby:

 …powerful nonmedical forces may also lead to enthusiasm for screening, including financial interests from companies that make tests or testing equipment or sell products to treat the conditions diagnosed and more subtle financial pressures from the clinicians whose daily work is to diagnose or treat a condition. If fewer people are diagnosed with a disease, advocacy groups stand to lose contributions and academics who study the disease may lose funding. Politicians may wish to appear responsive to powerful special interests…

While she may be right, that there are some influential and self-serving interests and corporations who push aggressively, and maybe too aggressively for cancer screening, it may also be that some forms of cancer screening are indeed life-saving tools that should be valued by our society. I think, also, that she goes too far in insinuating that major advocacy groups push for screening because they stand to lose funding.

I’ve met many cancer agency workers, some founders, some full-time, paid and volunteer helpers – with varied priorities and goals – and I honestly believe that each and every one of those individuals hopes that the problem of cancer killing so many non-elderly individuals in our society will go away. It’s beyond reason to suggest there’s a hidden agenda at any of the major cancer agencies to “keep cancer going.” There are plenty of other worthy causes to which they might give their time and other resources, like education, to name one.

Which leads me back to the original paper, on doctors’ limited knowledge –

As I read the original paper the first time, I considered what would happen if you tested 412 practicing primary care physicians about hepatitis C screening, strains, and whether or not there’s a benefit to early detection and treatment of that common and sometimes pathologic virus, or about the use of aspirin in adults with high blood pressure and other risk factors for heart disease, or about the risks and benefits of drugs that lower cholesterol.

It seems highly unlikely that physicians’ uncertainty is limited to conceptual aspects of cancer screening stats. Knowing that, you’d have to wonder why the authors did this research, and why the editorial pushes so hard the message of over-screening.

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Harsh Words, and Women’s Health at Risk

I’ll open with a confession –

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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50-50, A Serious Film About a Young Man With a Rare Cancer

scene from "50/50"

The other evening I watched 50/50, a film about a 27 year old man with a rare kind of cancer, a malignant schwannoma. The tumor is growing and pushing into the protagonist’s lower spine. The movie, based in part on the true story of scriptwriter Will Reiser, surprised me by its candor.

Actor Joseph Gordon-Levitt smoothly portrays Adam Lerner, who soon finds out he has cancer. The opening scene captures him jogging in an early morning. He seems a nice, cautious and perceptive young man in a relationship. His rowdier buddy, played hardily by Reiser’s real-life friend Seth Rogan, proves loyal during Adam’s chemotherapy and, later, big spine surgery.

By its cast, I expected this might be a guys’ flick. Yes, there are jokes about sex and cancer. But the film reveals the young man wincing during sex because he’s in pain and can’t hide it. The young women are pretty much all attractive, but they’re not interchangeable props; the relationships are complicated and plausible.

An unexpected perk in the movie is the realistic family dynamic. Lerner’s mother, a worrying sort, wants to be there for her son and doesn’t trust that his girlfriend will sufficiently help him. Anjelica Huston effectively fills the mother’s role. Lerner rarely answers her calls, while she’s biding her time with a husband who, due to Alzheimer’s, doesn’t comprehend what’s going on. She respects her son’s privacy, but feels, understandably, isolated and scared.

The doctors are flawed, of course. The oncologist at the start doesn’t directly tell Lerner of his diagnosis but, instead, speaks into a dictaphone about the malignancy. He refers Lerner to an analyst of some sort, a young woman with little experience, for talk therapy.

When Lerner goes for surgery, the pre-op scene is frighteningly realistic to anyone who’s ever had a young family member go through this kind of surgery. The family and friends are worried. The patient, calmest of all among the group, can’t determine what will be his fate.

The term schwannoma derives from Schwann cells. These elongate cells normally envelop long nerves and rarely become malignant. Most schwannomas, or neurofibromas, are benign; these can cause pain and other symptoms by pressing on nerves, but don’t usually don’t spread or grow quickly. The names can be confusing, as there are several similar-sounding terms for these growths. Some people inherit a disposition to these non-malignant tumors. Rarely, as seems to have been the case in this story, a schwannoma takes an aggressive, invasive and sometimes lethal course. Another name for the cancerous form is malignant peripheral neural sheath tumor, or MPNST.

50/50 refers to the odds of Lerner’s survival, about which he read somewhere on the Internet shortly after his diagnosis. I’d give the movie a high score, 90+, mainly for its lucid, accessible approach to a cancer patient’s experience and concerns.

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