Today’s Press on Targeted Therapy for Cancer

Today the NY Times printed the third part of Amy Harmon’s excellent feature on the ups and downs and promise of some clinical trials for cancer. The focus is on a new drug, PLX4032, some people with melanoma who chose to try this experimental agent, and the oncologists who prescribed it to them.

What I like about this story is that, besides offering some insight on the drug itself, it balances the patients’ and doctors’ perspectives; it explains why some people might elect to take a new medication in an early-stage clinical trial and why some physicians push for these protocols because they think it’s best for their patients.

And it provides a window into the world of academic medicine, where doctors’ collaborate among themselves and sometimes with corporations.

Here’s some of what I learned:

PLX4032 is a targeted therapy, a drug that’s designed to interfere with a specific, disease-causing molecular abnormality. It’s a small compound, taken by mouth, manufactured by Plexxikon that alters BRAF activity.

BRAF is a cellular enzyme, or kinase, that normally regulates how cells grow and divide. It’s encoded by an oncogene, a segment of DNA that can cause cancer when overly-expressed.

In most but not nearly all cases of melanoma, and in some other cancer clones, the malignant cells bear a mutated BRAF gene. This change can lead to a perpetually “turned on” state in the cells’ signaling machinery by which they proliferate without control. It’s thought that when PLX4032 works, it does so by blocking BRAF-mediated signaling and growth activity.

Harmon’s piece is long but easy to get through. She covers the human side of the story realistically. Some of the patients she describes with advanced tumors are desperate. The oncologists are, for the most part, hard-working idealists who work tirelessly for their patients.

There are real issues here, as in the setting of most clinical trials. I recommend this series to anyone who contemplates enrolling in a new drug study.

A remarkable point, as reported, is that the patients who ultimately succumbed to melanoma after a long period weren’t angry. As described, they didn’t feel “used” by their doctors or otherwise. Rather, they expressed appreciation. If these reported feelings are representative, that’s a testament to the quality of the care they received on study and, perhaps even more so, to effective communication between the patients and their physicians.

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New Boss on The Office is a Breast Cancer Survivor

Jo's mock-biography (NBC, The Office)

There’s a new survivor on TV and she means business.

In the latest episode of The Office, Kathy Bates walked into the Scranton branch of Dundler Mifflen and onto my living room TV screen as Jo Bennett, CEO of Sabre, a fictitious Tallahassee-based company. An assistant and two large canines accompany her as she meets the crew. She’s firm, graying and very much-in-charge.

When the camera gets her alone, in focus, here’s what she has to say:

“I’m Jolene Bennett, Jo for short.

I’m a breast cancer survivor, close personal friends with Nancy Pelosi, and Truman Capote and I slept with three of the same guys. When I was a little girl I was terrified to fly, and now I have my own pilot’s license.

I am CEO of Sabre International and I sell the best damn printers and all-in-one machines Korea can make.

Pleased to meet ya.”

(from The Office, Season 6, Episode 16, “A Manager and a Salesman”)

—–

Jo’s words are clear, delivered with eyes straight at you. It’s hard not to wonder what’s the significance of her being a breast cancer survivor, on the show and to her audience, and why she lists this alongside her other achievements in a highly-accomplished, fabricated life.

Kathy Bates is not the first actress to portray a woman who’s had breast cancer, and Jo Bennett is hardly the first TV character who’s had treatment. But this introduction seems like a perfect, even targeted strategy to revisit the topic:

What’s the significance of being a breast cancer survivor in 2010?

Maybe Jo’s a warrior, veteran-like, hardened after battle. Or perhaps wounded, deeply, now guarded by the dogs and a fierce resume.

Does she feel entitled? Bitter? Seek pity? Bates doesn’t play it in any of these ways, at least not in this first airing.

There’s no Misery here. Rather she appears large, strong, smiling broadly.

She has a mock-biography, Take a Good Look, I’d like to read. From the pseudo-Sabre website:

“A trailblazer in the world of electronic office equipment, Jolene Bennett serves as the President and Chief Executive Officer of the Sabre Corporation…Mrs. Bennett has received awards and recognitions, including being named one of Enterprising Women‘s Magazine 25 Most Influential Executives of 2007 and being named as a finalist for Tallahassian of the Year by the editors of Tallahassee Magazine in 2005.

Mrs. Bennett, a former Southern beauty queen, knows the importance of giving back. She has also received numerous awards for her philanthropic efforts with, among others, the Negro College Fund, The Florida Great Dane Rescue Society, and the American Breast Cancer Foundation. As a breast cancer survivor herself, Mrs. Bennett is especially passionate about helping other strong women beat cancer the way she did…

Jo’s company’s name is pointed. A sabre is a sword of sorts, usually curved, thick and sometimes lethal. My mind wanders to saber-toothed tigers, ferocious and extinct. And then, of course, to the Sabra, a native Israeli like a prickly pear – sharp on the outside, sweet beneath the rough skin.

I have no idea where The Office is headed with this theme, nearly ten years since Barbara Ehrenreich’s “Welcome to Cancerland” and roughly five since Elizabeth Edwards started her first chemo sessions.

I’m struck by how little talk there’s been of Jo’s mission since the episode’s debut. I’ve read dozens of blogs, TV reviews, there’s nothing. The Great Danes get mentioned, but not the breast cancer. Are we inured to the subject?

This isn’t about big Pink and ribbons. I’m talking about real patients who get tumors and need treatments. Some get depressed. Some die. Stuff happens.

As an oncologist, I saw women respond distinctly to their surgeries, radiation, chemotherapy and other treatments. Besides, the tumors vary in themselves – responding, sometimes lingering, killing too often. Some people need lots of medical care, others skate through.

There’s no right answer here, no one size fits all.

Regardless, I can’t wait to see the show’s next episode. Pam’s having a baby, life goes on.

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News on Aspirin After Breast Cancer

There’s some astonishing news on the breast cancer front.

A study published on-line this week in The Journal of Clinical Oncology (JCO) suggests that regular, low-dose aspirin use reduces the risk of recurrence and death from breast cancer among women who’ve had stage I, II or III (non-metastatic) disease.

This is a phenomenal report in three respects:

1. The dramatic results: among women who’ve had breast cancer, regular aspirin use is associated with a reduced risk of recurrence and death from cancer by more than half;

2. The relevance; these findings might affect millions of women living after breast cancer, today;

3. The cost: aspirin is widely available, without patent restriction. Aspirin costs around $5 for 100 tablets, several months’ supply.

About aspirin:

First, a concern that’s cited in the report:

Aspirin is an old and generally safe drug, available over the counter, that can be very dangerous in people with have bleeding problems or low platelets (blood clotting cells). Among women with breast cancer who are actively undergoing chemotherapy, radiation and some other treatments, aspirin use can exacerbate bleeding problems and may be inadvisable.

Anyone who considers taking aspirin should discuss, first, with their doctor if it’s OK.

The study participants reported taking aspirin (acetylsalicylic acid, or ASA in medical parlance) at varying doses and for a variety of reasons. More than a third of the breast cancer survivors used aspirin for heart disease. In that scenario, the typical dose is a baby aspirin (81 milligrams) on most days. Other women reported they took the drug for muscle and joint pains, backaches, headaches and other reasons.

About the study:

The work derives from the Nurses’ Health Study, a three-decades-and-going-strong observational analysis of health among over 238,000 registered nurses.

This particular analysis hones in on 4,164 of those nurses who had non-metastatic breast cancer (BC) found between 1976 and 2002. The investigators monitored these post-breast cancer patients with periodic questionnaires until the time of their death or 2006. It’s a large study, involving some 45,139 person-years.*

About the findings:

Figure 1. Aspirin Use and Relative Risk of Death from Breast Cancer

Aspirin Use, Relative Risk for Death from Breast Cancer

These graphs represent data from “Aspirin Intake and Survival After Breast Cancer,” JCO, Holmes, et al,  published on-line 2/16/10. The data are listed in Tables 2 and 3 of the paper, multivariate analysis, with 1.0 as the relative risk for women who had breast cancer and do not take aspirin (ASA).

Figure 2. Aspirin Use and Relative Risk of Breast Cancer Recurrence

Aspirin Use, Relative Risk of BC Recurrence.

Among BC survivors who reported taking aspirin between 2 and 5 days per week, the chances of dying from breast cancer were 29 percent relative to the baseline (no ASA) group and the odds of BC recurring, 40 percent. In other words,  aspirin use was associated with a 71 percent decline in deaths from breast cancer and a 60 percent drop in the recurrence rate for these women.

For those who ingested aspirin 6 or 7 days per week, the effects were similar: the death rate from cancer was 36 percent and the recurrence rate 57 percent, both significantly reduced in comparison to women who didn’t use aspirin. Among survivors who used 0-1 aspirin tablets per week, there was no measurable effect on either breast cancer recurrence or survival.

The results applied pretty much across the board – to premenopausal and post-menopausal women, to those with Stage I, II, and to a lesser extent, Stage III disease and to survivors with estrogen receptor positive (ER+) and negative (ER-) tumors.

The findings were not anticipated, according to the investigators, because earlier studies failed to show that aspirin prevents breast cancer from developing in the first place. What’s different here, they speculate, is that aspirin inhibits some inflammatory molecules, like prostaglandins or cyclooxygenases. The authors suggest these enzymes promote growth and metastatic spread of tumors that are already present.

Some details:

The study statistics are sound, with good (low) p-values for the aspirin-use trends, meaning that the likelihood of the observations being due to chance is extremely low. There are some limitations: first that the trial was not randomized, and second, that the reported use of aspirin was based on survey data provided by the nurses. But the size of the study, involving more than 4000 women who had breast cancer, the duration of analysis (over decades) and the not-slight differences in results between the treatment groups speak to the significance and potential implications.

—–

*In this analysis, person-years would be defined as the sum, for all women registered in the study, of the years for which they’ve been monitored. For example if 3 women were evaluated, each for 10 years, the study would include 30 person-years of data.

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You’re Sick and I’m Not, Too Bad

“The insurance market as it works today basically slices and dices the population. It says, well you people with medical conditions, over here, and you people without them, over here…

– Jonathan Cohn, Editor of The New Republic, speaking on The Brian Lehrer Show, February 16, 2010*

There’s a popular, partly true, sometimes useful and very dangerous notion that we can control our health. Maybe even fend off cancer.

I like the idea that we can make smart choices, eat sensible amounts of whole foods and not the wrong foods, exercise, not smoke, maintain balance (whatever that means in 2010) and in doing so, be responsible for our health. Check, plus.

It’s an attractive concept, really, that we can determine our medical circumstances by informed decisions and a vital lifestyle. It appeals to the well – that we’re OK, on the other side, doing something right.

There is order in the world. God exists. etc.

Very appealing. There’s utility in this outlook, besides. To the extent that we can influence our well-being and lessen the likelihood of some diseases, of course we can!  and should adjust our lack-of-dieting, drinking, smoking, arms firing, boxing and whatever else damaging it is that we do to ourselves.

I’m all for people adjusting their behavior and knowing they’re accountable for the consequences. And I’m not keen on a victim’s mentality for those who are ill.

So far so good –

Last summer former Whole Foods CEO John Mackey offered an unsympathetic op-ed in The Wall Street Journal on the subject of health care reform. He provides the “correct” i.e. unedited version in the CEO’s blog:

“Many promoters of health care reform believe that people have an intrinsic ethical right to health care… While all of us can empathize with those who are sick, how can we say that all people have any more of an intrinsic right to health care than they have an intrinsic right to food, clothing, owning their own homes, a car or a personal computer? …

“Rather than increase governmental spending and control, what we need to do is address the root causes of disease and poor health.  This begins with the realization that every American adult is responsible for their own health.  Unfortunately many of our health care problems are self-inflicted…

Now, here’s the rub. While all of us can empathize, not everyone does. And few citizens go to medical school. Some, uneducated or misinformed, might sincerely believe that illnesses are deserved.

So let’s set some facts straight on real illness and would-be uninsurable people like me:

Most people who are sick – with leukemia, diabetes, osteogenesis imperfecta, heart disease, multiple sclerosis, scoliosis, glycogen storage disease Type II, depression, Lou Gehrig’s disease, sickle cell anemia, rheumatoid arthritis or what have you – are not ill by choice. They didn’t make bad decisions or do anything worse, on average, than people who are healthy.

Rather, they became ill. Just like that.

The idea of an insurance pool is that when everyone in the community participates, whoever ends up with large medical expenses is covered, explained Jonathan Cohn. When contributions come in from all, including those who are healthy, funds are sufficient to provide for the sick among us.

As things stand, the insurance industry divides us into likely profitable and unprofitable segments. “So you know if you’re one of the people born with diabetes, you have cancer, you had an injury that requires lengthy rehabilitation, tough luck, you’re going to end up in that pool of unhealthy people,” Cohn said.

Insurance is no cure-all, to be sure. It won’t take away my cousin’s cancer or fix Bill Clinton’s heart. That would require research and better medicines.

Depriving insurance, or care, to those who need it most is inconceivable to a society as ours was intended. It’s uncivil.

*as heard on The Brian Lehrer Show 2/16/10: Rates on the Rise

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Health Care Costs, Communication and Informed Choices

For those of you who’ve been asleep for the past year: the health care costs conundrum remains unsolved. Our annual medical bills run in the neighborhood of $2.4 trillion and that number’s heading up. Reform, even in its watered-down, reddened form, has stalled.

Despite so much unending review of medical expenses – attributed variously to an unfit, aging population, expensive new cancer drugs, innovative procedures, insurance companies and big Pharma – there’s been surprisingly little consideration for patients’ preferences. What’s missing is a solid discussion of the type and extent of treatments people would want if they were sufficiently informed of their medical options and circumstances.

Maybe, if doctors would ask their adult patients how much care they really want, the price of health care would go down. That’s because many patients would choose less, at least in the way of technology, than their doctors prescribe. And more care.

What I’m talking about is the opposite of rationing. It’s about choosing.

Several recent stories have considered the problem of physicians not talking with their patients about treatment limits. Last month the journal Cancer published a study, based on canvassing over 4000 doctors who care for cancer patients in California, North Carolina, Iowa and Alabama, revealing that only a minority of physicians would raise the subject of a DNR order or hospice care for patients with metastatic cancer and a short life expectancy.

When it comes to recommending palliative care, aimed at patients’ nutrition and comfort, rather than cure, some doctors remain tight-lipped. Many good physicians, including cancer specialists, are reluctant to stop prescribing chemotherapy and aggressive treatments. The reasons vary. Based on my experience as a practicing oncologist, I’ll list a few:

Some doctors think it’s better for their patients if they are upbeat, and this may indeed be true. Conversely, many patients choose doctors who are optimistic: if you tell patients there are no treatment options, they’ll go elsewhere. Most patients, of course, do want treatment; more than a few are desperate enough to try anything a doctor says might work.

Another, unfortunate factor is financial pressure; giving treatment and doing procedures is far more lucrative than simple exam and discussion-based visits. I’m afraid, too, that many physicians don’t recognize the extent they’re influenced by effective marketing, usually blatant but sometimes subtle.

For others it’s an ego thing – doctors try to “outsmart” a disease, even when it’s not feasible, trying one therapy and the next, to no avail.

Harder to assess, still, is doctors’ internal unwillingness to give up on some patients because they care about them so much. Some excellent doctors may become so invested in a case that they, themselves, cannot be objective.

Besides, “throwing in the towel” is not something most good doctors like to do. And it’s not something most patients want to hear about.

Yet, maybe some dying patients would appreciate a doctor’s honesty –

These issues relate directly to the practice of oncology, the area of medicine I know best. But similar hesitations and conflicts of interest arise among doctors in most fields – cardiologists caring for people with severe heart disease, neurologists caring for people with end-stage Parkinson’s, and infectious disease experts caring for people with late-stage HIV, to name a few.

If doctors could somehow find the time, and take the trouble, to talk with their patients in a meaningful way, and then heed their patients’ wishes, they might find that many patients would, of their own volition, put a brake on health care spending.

For this reason, among the changes in health care I most favor is greater support for primary care and non-procedural services. If  were paid more for thinking and communicating, rather than ordering tests and performing treatments in a perfunctory manner, they and their patients might opt for less expensive, more humane remedies.

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On Precious

This is my first film review, if it is that.

I was tempted to write about Ethan Hawke, hematologist among vampires in Daybreakers, but gore’s not my favorite genre. A mainstream choice would have been Harrison Ford solving the enzyme deficiency of Pompe disease in Extraordinary Measures, but I didn’t get sucked in. I chose Precious, instead.

Poster for Precious, the film based on the novel “Push,” by Sapphire

This luminous movie relates to the practice of medicine everyday, big-time. Directed by Lee Daniels and based on the novel Push by Sapphire (Ramona Lofton), the film follows a very obese Harlem teenager who’s pregnant with a second child by her abusive father. She’s humiliated daily by her welfare-dependant mother who forces her to cook greasy food and perform sexual acts all-the-while telling her she’s worthless. She’s 17 years old and can’t read. Things can get worse, and do.

What’s relevant to medical lessons?

For doctors –

The message of Precious, that every human life has value, should be obvious to every person employed in the health care system. But I know too well that’s not true.

When I was a medical student in 1985, working with a team of surgery residents, we cared for an obese young woman from Harlem who came in with a life-threatening case of pancreatitis. Her internal insulin-manufacturing organ was so inflamed that her entire gigantic abdominal cavity was tender and bloody. During what seemed like an endless operation in the middle of the night I stood and held firmly a retractor as best I could. The next morning and thereafter, when we made rounds, the residents called her “the whale.”

I learned a lot about pancreatitis and surgery that month. But I couldn’t understand how she, my patient, tolerated the team’s attitude. She didn’t seem to mind, perhaps because we saved her life and the care we provided was free. In retrospect, I wonder if maybe, like Precious, she was too-accustomed to disrespect.

Of course, this is an extreme example from 25 years ago. And I know from my experience working for years in a hospital, and in my years as a patient, that most doctors treat most patients with appropriate dignity. But those residents I worked with then are senior practicing physicians now, likely some on the faculty of medical schools. The disposition to disparage patients, more often subtly – in keeping them waiting without good reason, in dismissing their long lists of real concerns, in somehow putting ourselves above them and even, still, occasionally expressing frank contempt for some unfortunate souls still permeates the hospital culture.

For patients –

When Precious is abused, her mind runs elsewhere. She imagines herself, huge body and all, cast glamorously among television stars or dancing with popular singers. She pretends that she’s all right even when she’s not, really. Finally she speaks up for herself, telling a social worker about her predicament.

Ultimately that’s what makes the difference – her confidence in the value of her own bruised life. She recognizes that, despite everything, she’s a full-fledged human deserving better and has the guts to ask for help. By insisting, by knowing, that her life matters, she pushes herself out, if only partly, from the bleakest of circumstances.

If you’re disabled, hurt, wounded, damaged – ask for help when you need it. Respect yourself, as Precious did. That sends a signal to doctors that you value your life, and they should treat you accordingly.

Hopefully they’ll be paying attention.

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Henrietta’s Cells Speak

“One of the ways that I gained the trust of the family is that I gave them information.”

(R. Skloot, a journalist, speaking about her interactions with Henrietta Lacks’ family, Columbia University, Feb 2, 2010)

This week I had the opportunity to hear a terrific talk by Rebecca Skloot, author of a new, flying-off-the-shelves book –The Immortal Life of Henrietta Lacks.

Mrs. Henrietta Lacks died of metastatic cervical cancer in the colored ward at Johns Hopkins Hospital in Baltimore, MD in September 1951. She lived no more than 31 years and left behind a husband, five children and an infinite supply of self-replicating cancer cells for research scientists to study in years to come.

HeLa cells with fluorescent nuclear stain (Wikimedia Commons)

Like many doctors, I first encountered HeLa cells in a research laboratory. Investigators use these famous cells to study how cancer cells grow, divide and respond to treatments. I learned about Mrs. Lacks, patient and mother, just the other day.

Skloot chronicles her short life in fascinating detail. She contrasts the long-lasting fate and productivity of her cells with that of the woman who bore them. She connects those, and her human descendants’ unfortunate financial disposition, to current controversies in bioethics.

In the years following their mother’s death, scientists repeatedly approached her husband and asked her young children for blood samples to check the genetic material, to see if their DNA matched that of cell batches, or clones, growing in research labs.

The issue is this: her husband had but a third-grade education. The children didn’t know what is a “cell,” “HLA-testing” or “clone.”

The family had essentially no idea what the doctors who’d taken, manipulated and cloned their mothers’ cells were talking about, Skloot recounts. They thought the doctors were testing them for cancer.

Years later, when they learned that their mother’s cells were bought, sold and used at research institutions throughout the world, they became angry and distrustful. The problem was essentially one of poor communication, she considered.

“Even a basic education in science would have helped,” Skloot said. “Patients, they want to be asked, and they want to be told what’s going on.”

Well said!

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Are Doctors Necessary?

Ten years ago, my colleagues and I squirmed in our swivel chairs when a few tech-savvy patients filed in bearing reams of articles they’d discovered, downloaded and printed for our perusal. Some of us accepted these informational “gifts” warily, half-curious about what was out there and half-loathing the prospect of more reading. Quite a few complained about the changing informational dynamic between patients and their physicians, threatened by a perceived and perhaps real loss of control.

How a decade can make a difference.

In 2000 the Pew Charitable Trusts initiated the “Internet & American Life Project” to explore how the Web affects families and communities in matters of daily life. Susannah Fox is an associate director of the Research Center project.

“It’s the ultimate information appliance” she says of the Internet. Now that it’s in most people’s homes, people use it as they choose.

And that’s quite often –

In 2008 over 140 million Americans, a majority of U.S. adults, looked for health information on-line, according to the Center’s 2009 report. Nearly 60 percent of those admit that a recent Internet search influenced a medical decision.

“Back in 2000, our data was used to prove the concept that people were going on-line to get heath care information,” she says. But that’s no longer the issue.

“With Facebook, MySpace and Twitter, there’s a new frontier” she states. “I think we’re at a new inflection point, and now is the time to have a very clear conversation on health care.

There’s been a significant shift on the physicians’ side, too.

“It’s become clear that increased communication and discussion can change care in a positive way” says Dr. Barron Lerner, a primary care physician and medical historian at Columbia University. His most recent book, When Illness Goes Public: Celebrity Patients and How We Look at Medicine, considers how ailments in the public realm can influence peoples’ perception of illness and inform their care choices.

“The Internet can be amazingly good to get people up and running” he considers. Lerner encourages his patients who have cancer to visit the National Cancer Institute (NCI) website.

“Why not go on, and explore,” he tells them. “Now as for how much they can absorb there, I don’t know,” he adds. “It’s a very hard website.”

Dr. Gretchen Berland is a primary care physician, videographer and former MacArthur Foundation fellow at the Yale University School of Medicine. She led an early study on the quality and accessibility of web-based medical information in that was published in the Journal of the American Medical Association in 2001.

“The Internet gives people a sense of control,” she says. “People use the Web to augment the information they’re given by their physicians, to look for a second opinion, and to search for clinical trials.”

But despite the wealth of information, and good quality of many sites, Berland sees limits in the Internet’s use, particularly for patients with complex, serious conditions like cancer. Even if online materials are comprehensive and accurate, they rely on people’s ability to find and understand them.

The Internet is not enough to help most people, she states.

Recently Berland searched on-line resources on behalf of a friend who had cancer surgery. When she looked at all the data, including material gleaned from some physician-oriented sites, there were gaps. “It wasn’t clear what he should do, despite how much information is out there.”

That’s the paradox of the Internet, she notes. “It’s hard to know what applies to a particular person’s unique and complex medical circumstances.

“One thing the Web doesn’t do is personalize the information,” she says. “That’s what physicians do.”

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