Brief Report: Annual Meeting of the Metastatic Breast Cancer Network

The Metastatic Breast Cancer Network held its fifth annual meeting in Baltimore over this past weekend. Most of the nearly 300 registrants were women living with MBC.

The lively group of women coalesced in the face of unexpected, pre-seasonal wintry weather. At an evening reception they stood, sat, waited for drinks and lined up for buffet food. Some lingered, chatting at round tables for well over an hour beyond the party’s official end-time. Over breakfast and lunch breaks the next day, there was plenty of reconnecting, hugs and catching up.

Like other medical conferences, there were plenary and breakout sessions on the educational program. You could choose, for example, between panels on “Treatment of Bone Metastases,” “Role of Surgery in Soft Tissue Mets” and “Managing Side Effects.”  Later, fuzzier and perhaps more intense sessions covered “Role of the Caregiver,” “Nutrition and Wellness” and a “Living with MBC.” Plenary talks ranged from introductory, light remarks to hour-long lectures on breast cancer immunotherapy, clinical trials and epigenetics. I took extensive notes.

Two highlights from this noteworthy gathering:

In introductory remarks shortly after 9AM, MBCN Board member Shirley Mertz recalled attending her first conference of this group, and the feelings she experienced upon meeting other women in similar straits. Her message was this: “Take a look around, you are not alone.”

Late in the day Dr. Stephen Baylin, a professor of oncology and medicine, prefaced his talk as follows: “It’s a privilege – talking with you, hearing what the disease is like, hearing your questions.” He was standing at the podium of Turner Auditorium at Johns Hopkins. “Please teach me,” he said – rare words emanating from the front of a prestigious medical school lecture hall.

Indeed, there’s a lot a doctor might learn at a conference like this. I did, for sure.

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Arizona Cheerleaders Cause Community Stir With Breast Cancer Awareness Shirts

This story, shared today by Debbie Woodbury, warrants ML Annals of Pink inclusion:

The Arizona Republic reports on a divided community in Gilbert, AZ. At issue is the high school cheerleading team’s plan to wear pink tee shirts with the slogan: “Feel for lumps – save your bumps” on the back. The group’s intention was to raise awareness and funds for the Susan G. Komen Foundation. 

The school’s principal said no to the controversial outfits due to their “unacceptably suggestive” content.

What strikes me, among other interesting aspects of this story and what it reflects about BC awareness in 2011, is how the arguments (so needless!) about fundraising play out so differently, depending where you live and the newspapers you might read.

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Mammograms Could Save More Lives Than You Might Think

I’m wondering is how to bring mainstream health journalists and women who are, lately, choosing not to have mammograms, to their senses about a persuasive but flawed argument put forth by a Dartmouth epidemiologist and others in a crew of seemingly like-minded, hopefully well-intentioned, some perhaps tenure-seeking and others grant-needing, circulatory bias-confirming academics who meet and discuss and write about the so-called dangers of mammography.

Maybe some doctors and journalists think they’re doing the right thing by informing a naïve body of women who, in the words of an LA Times writer today, think only correlative and simple thoughts.

From Screening mammograms save fewer lives than you think:

If you or someone you know discovered she had breast cancer thanks to routine mammography screening, and if you or that friend with breast cancer got treatment and today is cancer-free, it’s natural to assume that the mammogram was a life-saver.

But odds are, it wasn’t….

First things first: the title makes an assumption about what I, or you, or any reader, thinks.

Second, the story offers two factoids: first – that over 75% of women diagnosed with BC by screening mammography wouldn’t have died from the cancer if they hadn’t had mammography; and second – that no more than 25% of those same women can rightly credit a mammogram for saving their lives. But this is just one stat, or falsehood, based on the true, assumption-free relationship between 75% and 25%.

Dr. H. Gilbert Welch, who recently likened mammography-taking to gambling, plays freely with impressive-sounding information sources. He and his coauthor used data from the NCI. Seemingly hard to argue with those kinds of numbers. But they used old data, again, and employ numerous assumptions (what the authors call generous, but I wouldn’t) to render calculations and “prove” their point published in the Archives of Internal Medicine.

The manipulative tone is set in the paper’s abstract:

“…We created a simple method to estimate the probability that a woman with screen-detected breast cancer has had her life saved…

Simple? Don’t you believe it.

There’s a Well post in the New York Times today covering the same Archives of Internal Medicine article. Not surprisingly, this draws positive feedback in the comments and Twitter-chatter. Some of the more understandable discussion comes from women with metastatic disease whose tumors were missed by screening mammography. Notably, neither paper quotes an oncologist.

Here in the U.S. where we do spend too much on health care, we all know women whose breast tumors were missed by screening mammograms. This happens, and it’s awful, but it doesn’t and certainly shouldn’t happen so often as some doctors seem to think. Extrapolating from personal observations to draw conclusions about a procedure’s value is flawed reasoning, either way.

I agree with many of Dr. Susan Love’s school, and most of the NBCC agenda, and others that say breast cancer prevention would be better than treatment. How could I not?

But until there’s a prevention for BC, which I’m sorry to report is unlikely to happen before 2020, especially because it’s really 15 or 20 or maybe even more diseases that would, presumably, need distinct methods of prevention, and until there are better, less damaging and less costly remedies, mammography may be the best way for middle-aged women to avoid the debilitating and lethal effects of late-stage disease. And for society to avoid the costs of that condition and its treatments, which are huge.

—-

post shortened 12/18/12

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3 Differences between Prostate and Breast Cancer Screening

Days ago, the USPSTF issued a new draft for its recommendations on routine PSA measurements in asymptomatic men. The panel’s report is published in the Annals of Internal Medicine. The main findings are two: first, the absence of evidence that routine PSA testing prolongs men’s lives, and second, that PSA evaluation may, on balance, cause more harm than good.

Not surprisingly, there’s been considerable coverage of this by the media, and some controversy. For decades, many men have had their PSA checked, knowingly or not, by their physicians. The PSA test  measures the level of Prostate Specific Antigen, a protein produced and sometimes secreted by prostate cells, normal, inflamed or malignant, into the bloodstream.

As an oncologist, I don’t find the panel’s recommendations surprising. There’s never been strong data to support the hypothesis that routine PSA testing reduces mortality for men in any age group. Prostate cancer is often indolent, a slow-growing kind of tumor for which a “watch and wait” approach may be best, especially when it occurs in elderly men who are most likely, even in the absence of treatment, to die of another cause. The complication rate of prostate surgery is fairly high, although this “cost” of screening likely varies, depending on the skill of the surgeon. Still, and understandably, there are men who swear by this measurement, whose lives have been, in some cases, saved by early detection of a high-grade tumor upon screening.

For today, I’d like to consider some key differences between breast and prostate cancers, and the potential value of screening:

1. Breast cancer tends to affect younger patients than prostate cancer.

Based on SEER data, the median age of a breast cancer diagnosis in the U.S. is 61 years. The median age of death from breast cancer is 68 years. For prostate cancer, the SEER data show a median age of 67 years at diagnosis, and for death from prostate cancer, 80 years.

So the potential number of life-years saved by early detection and intervention is, on average, greater for breast cancer than for prostate cancer.

2. Screening for breast cancer has improved over the past 25 years.

Because the blood test for PSA hasn’t changed much in decades, it’s reasonable to consider studies and long-term survival curves based on data going back to the 1980s.

Mammography, by contrast, is much safer and better than it was 25 years ago, for various reasons: increased regulation of mammography facilities (more care with the procedure, better training and credentialing of technicians) according to the FDA’s Mammography Quality Standard Acts Program ; development of ultrasound methods to supplement mammograms in case of suspicious lesions (lessens the false positive rate overall); the advent of digital technology (lessens the false positive rate in younger women and others with dense breasts); more breast radiology specialists (expertise).

The data reviewed by the USPSTF in issuing their 2009 recommendations for BC screening were decades old, and, as I’ve considered previously, irrelevant to modern medical practices. A recent article in the NEJM points to the problem of the panel’s reliance on the Age trial for women in their 40s. That trial involved the obsolete method of single-view mammography.

3. Mammography involves a woman’s consent (in the absence of dementia – a separate ethical issue).

A woman knows if she’s getting a mammogram. She may not ask sufficient questions of her doctor, or her doctor may not answer them well, but in the end she does or doesn’t enter into a radiology room, volitionally. She decides to get screened, or not. She can choose to have a mammogram every year, or every other year, or not at all.

There’s no ethical problem, as reported for some men, of patients learning they have an abnormal PSA, after blood was drawn indiscriminately, without their knowing the test was being performed.

This perspective might, and should, later extend to consider additional differences between these two kinds of malignancies (each of which is really a group of cancer subtypes), a fuller discussion of the impact of treatment on survival for each type, and the relative risks of screening due to differential complication rates of biopsies and other procedures.

To be clear, there’s no perfect screening test for either cancer type. Far from it. But the merits and risks of each procedure should be weighed separately, and with care.

All for today.

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What Is a Cancer Metastasis?

A metastasis refers to a lump of cancer cells that’s physically separated from the original tumor. A metastasis can be local, like when colon cancer spreads to a nearby lymph node in the gut, or distant, as when lung cancer cells generate tumors in the adrenal gland, liver, bone or brain.

Sometimes metastases cause serious damage in the organs where they’ve settled. For instance, brain “mets” can result in impaired thinking, personality changes, blindness or seizures. Liver metastases, if large enough, can result in hepatic (liver) failure. Bone mets can lead to anemia and other blood cell deficiencies if the marrow becomes filled with malignant cells instead of normal ones.

A common source of confusion is that when cancer moves from one body part to another, it’s still referred to by its site of origin.  For example, if breast cancer spreads to the liver or bone, it is still called breast cancer and most often treated as such. In general it’s the type of malignant cell, rather than the affected organ, that guides therapy.

Notes on usage: The plural is “metastases.” When someone has metastatic disease, that means their cancer has spread from the primary site to another. Oncologists don’t usually apply these terms to leukemia or lymphoma.

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More on DCIS

More, a magazine “for women of style & substance,” has an unusually thorough, now-available article by Nancy F. Smith in its September issue on A Breast Cancer You May Not Need to Treat.

Ductal Carcinoma in Situ (DCIS) in the breast, histopathology w/ hematoxylin & eosin stain, Wiki-Commons image

The article’s subject is DCIS (Ductal Carcinoma in Situ). This non-invasive, “Stage O” malignancy of the breast has shot up in reported incidence over the past two decades. It’s one of the so-called slow-growing tumors detected by mammography; a woman can have DCIS without a mass or invasive breast cancer.

While some people with this diagnosis choose to have surgery, radiation or hormonal treatments, others opt for a watchful waiting strategy. The article quotes several physicians, including oncologists, who consider the surveillance approach favorably and otherwise.

In 2009 the NCI sponsored a conference on diagnosis and management of DCIS. The participants issued a helpful, albeit technical, consensus statement.

The bottom line is that optimal treatment for DCIS remains uncertain because doctors don’t yet know the natural course of this early-stage breast malignancy. The ClinicalTrials.gov website lists active and ongoing studies.

 

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Two Faces of Pancreatic Cancer

Early this week I was saddened to hear of a former colleague’s death from pancreatic cancer. Dr. Ralph Steinman, a physician-researcher at the Rockefeller University, received a Nobel Prize for his work on the innate immune system. For many, news of Ralph’s death at 68 years arrived synchronously with word of his award.

Yesterday we learned that Steve Jobs, Apple creator and leader, died at 56 years from a neuroendocrine tumor of the pancreas. The tech-based, Twitter-type tributes reveal the breadth of this man’s influence on our world.

These two men faced completely different forms of cancer in the pancreas. This news underscores the importance of pathology in cancer diagnosis and treatment. For a patient to make an informed treatment decision, which might be to decline treatment, a patient needs to know what kind of cancer they have, what is the prognosis, and how might therapy change the course of the particular illness.

Jobs had a neu­roen­docrine tumor. According to the NCI, islet cell tumors of the pan­creas are quite rare, with esti­mates of between 200 and 1000 new cases per year. These can be dis­tin­guished from other cancers by special stains and mol­e­cular tests. Just months ago, the FDA approved two new drugs for treatment of neuroendocrine tumors of the pancreas: Afinitor (Everolimus) and Sutent (Sunitinib).

This kind of cancer can arise in almost any body part, but it’s most commonly found in endocrine (hormone-secreting) organs. In the pancreas, it can develop from islet cells that manufacture hormones such as insulin. Symptoms may occur if the tumors secrete active hormones, with effects elsewhere in the body, or if they cause pain by expanding and pressing on nearby nerves, vessels or ducts. These tumors tend to grow slowly and the prognosis is relatively good; doctors may advise some patients to hold off on treatment until symptoms occur.

The usual form of pancreatic cancer is of the exocrine cells, those that produce and secrete digestive enzymes into the bile duct and small intestine. According to the American Cancer Society, there are over 44,000 new cases of pan­creatic cancer yearly in the U.S. It tends to occur in the elderly and is slightly more common in men. Cig­a­rette smoking is one of the few certain dis­posing factors; the causes are largely unknown. The prognosis for this kind of pancreatic disease remains poor, on average. Standard treatments, according to the NCI, include surgery, radiation, chemotherapy and palliative care.

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Glad to Spot a Pink Ribbon

This morning I walked into a Starbucks and noted a woman wearing a little pink ribbon on the lapel of her suit. She appeared to be in a meeting, speaking seriously with a small group of people dressed for business.

How great is that, I thought, that she wears the pink ribbon unabashedly, in this October of 2011. She sees nothing wrong with raising awareness about breast cancer, or expressing her concern about this killer of women. Kudos!

In some circles now it’s fashionable to bash pink symbols, to say how breast cancer shouldn’t be prettified, or commercialized, or overblown. What I’d say is, of course, the disease isn’t beautiful, or good, or inherently profitable, or to be perceived as a gift. It’s none of those things.

But we take for granted, lately, how open people are about breast cancer and its complications. Twenty years ago, and even ten, many women I knew took their treatments silently. Few disclosed their illness to others in the community. Many lacked open sources of information or support. For some, breast cancer was a source of shame.

Times have changed, indeed.

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NEJM Publishes New Review on Breast Cancer Screening

With little fanfare, the NEJM published a feature on breast cancer screening in its Sept 15 issue. The article, like other “vignettes” in the Journal, opens with a clinical scenario. This time, it’s a 42 year old woman who is considering first-time mammography.

The author, Dr. Ellen Warner, an oncologist at the University of Toronto, takes opportunity to review updated evidence and recommendations for screening women at average risk for the disease. She outlines the problem:

Worldwide, breast cancer is now the most common cancer diagnosed in women and is the leading cause of deaths from cancer among women, with approximately 1.3 million new cases and an estimated 458,000 deaths reported in 2008.(1)

On screening:

The decision to screen either a particular population or a specific patient for a disease involves weighing benefits against costs. In the case of breast-cancer screening, the most important benefits are a reduction in the risk of death and the number of life-years gained….

She breaks down the data for mammography by age groups:

For women between the ages of 50 to 69 the evidence is clear, she says. For those over 70, there are little data to support breast cancer screening. There’s a consensus that screening isn’t appropriate for women with serious coexisting illnesses and a life expectancy of less than 5-10 years.

For those between the ages of 40-49, Warner challenges the revised 2009 USPSTF recommendations on several counts. She critiques those authors’ weighting of data from the Age trial of 161,000 women, emphasizing the use of an antiquated (single view) mammography technique and flawed statistics. She considers:

…However, this change in remains highly controversial,22, 23 especially because of the greater number of years of life expectancy gained from preventing death from breast cancer in younger women. According to statistical modeling,19 screening initiated at the age of 40 years rather than 50 years would avert one additional death from breast cancer per 1000 women screened, resulting in 33 life-years gained.”

What I like about Warner’s analysis, besides its extreme attention to details in the data, is that she’s not afraid to, at least implicitly, assign value to a procedure that impacts a young person’s life expectancy relative to that of an older person.

She goes on to consider digital mammography and the Digital Imaging Screening Trial (DMIST [NCT00008346]) results. For women under 50 years, digital mammography was significantly more sensitive than film (78% vs. 51%).

The article is long and detailed; I recommend the full read including some helpful tables, with references to the major studies, and charts.

In concluding, the author, who admits receiving grant support from Amersham Health (a GE subsidiary), consulting fees from Bayer and lecture fees from AstraZeneca, returns to the hypothetical patient, and what might be said to a woman in her 40s who lacks an outstanding risk (such as a genetic disposition or strong family history):

…Mammography screening every 2 years will find two out of every three cancers in women her age, reduce her risk of death from breast cancer by 15%. There’s about a 40% chance that further imaging (such as a sonogram) will be recommended, and a 3% chance for biopsy with a benign finding….

In my opinion (ES) this is key – that the chances of a false positive leading to biopsy are only 3% for a woman in her 40s. If those biopsies are done in the radiology suite with a core needle, every 2 years for women of average risk, the costs of false positives can be minimized.

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1 in 70 Women Develops Breast Cancer Before Reaching 50 Years

A post in yesterday’s Well column, about coverage of breast cancer by the media, focused on the first-person narrative of NBC’s Andrea Mitchell. Journalist Tara Parker-Pope writes:

Her announcement has generated much discussion in the blogosphere, including an analysis by Gary Schwitzer, publisher of HealthNewsReview.org, who writes that Ms. Mitchell made some missteps in discussing her cancer.

The Times column goes on to consider what was said, and how it might have been said better, and I agree with much of it. But mainly it’s a meta discussion, journalists talking about how other journalists consider breast cancer facts, figures and narratives.

Buried deep is this number, that according to the NCI, one in 69, or for the sake of simplicity – approximately 1 in 70 – women in the U.S. will receive a diagnosis of BC in her forties. That is an astonishingly enormous proportion of women under 50 years affected by a devastating disease.

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Reducing Cancer Care Costs by Comparative and Cost-Effectiveness Research (CER)

Well, it’s the day after Labor Day, time to resume our discussion of Bending the Cost Curve in Cancer Care.

We’ve reached the end of the list, on ideas to reduce oncology costs put forth by Drs. Smith and Hillner in the May 25 issue of the NEJM. Really this 10th and final point intended for oncologists is two-in-one: “The need for cost-effectiveness analysis and for some limits of care must be accepted,” they chart. So doctors should embrace studies of comparative effectiveness and cost effectiveness.

Hard to argue with reason – they’re correct, of course. They write:

… The national imperative is to empower a transparent, acceptable, equitable, politically independent agency for guidance in making tough choices in the public interest so that doctors do not have to make them at the bedside.60 Ultimately, we will have to make decisions based on some criteria, and comparative-effectiveness61 and cost-effectiveness62 analyses are good ways to align resource use with the greatest health benefit.

This sounds great, and is probably right, but I don’t think it’s realistic.

A more detailed consideration on the issue of cost-effectiveness, IMO, came out a few weeks later, also in NEJM: Comparative Effectiveness Research and Patients with Multiple Chronic Conditions. This piece, by Drs. Mary Tinetti and Stephanie Studenski, considers the problematic application of CER in the real world.

The problem with CER, these authors emphasize, is that most medical patients have more than one condition and many are elderly; clinical trials tend to include, exclusively, patients who don’t have more than one major illness are relatively young. This limits the physicians’ abilities to apply data to their patients.

What’s more, reported results tend to focus on central results, but most patients fall elsewhere on measured curves:

The heterogeneity of treatment effects will further complicate CER. Although studies typically report average effects, most participants experience more or less benefit and harm than average. Such heterogeneity results from variability in patients’ initial level of risk for a given outcome, in their responsiveness to treatment, and in their vulnerability to adverse effects — issues with particular relevance to patients receiving treatment for multiple coexisting conditions.

The authors, who recognize the need for better research to support treatment decisions, write that “CER will probably accelerate the movement toward outcome-driven decision making, reimbursement, and quality assessment. As this shift occurs, we must move toward a focus on cross-disease, “universal” outcomes in research and clinical care.” Their thesis gets more abstract (which I admire), but meets a wall or two: the lack of consensus on a set of universal health outcomes, different parameters measured by the likes of the VA administration, CMS, the FDA, NIH and other huge agencies.

They make a practical suggestion, about the need for head-to-head comparisons in CER:

… interventions such as exercise that affect multiple conditions simultaneously should be a high priority…Studies should include assessment of the burden of treatments for patients and families. Another CER priority should be the examination of treatments for common pairs of diseases in which treatment of one may exacerbate the other. For example, when hypertension and osteoporosis coexist, what treatment best minimizes the risk of adverse cardiovascular outcomes without increasing the risk of falls and fractures?

All of this sounds reasonable to this patient-doctor, but it’ll take a lot of time and money to accomplish effective CER that encompasses the needs and conditions of sufficient numbers of patients in disease and age combinations to power any meaningful studies. You have to wonder at some point, as I have been lately, is all this clinical research worth the effort?

That said, I respect this paper‘s conclusions on CER:

Researchers have largely shied away from the complexity of multiple chronic conditions — avoidance that results in expensive, potentially harmful care of unclear benefit. We cannot improve health care’s quality, effectiveness, and efficiency without addressing its greatest consumers. Development and testing of innovative approaches to care for patients with multiple chronic conditions could prove the most lasting legacy…

My bottom line: CER, and consideration of treatment costs, should underlie reduction of cancer care costs in the near and long-term future. As to how we accomplish sufficiently careful research, and avoid inappropriate cutting of helpful treatments – especially those that prove beneficial for some younger and otherwise healthy cancer patients – is one of the two main challenges ahead.

(The other big challenge, mainly a moral one, is the subject of rationing, to which Smith and Hillner allude but don’t detail, and which subject I won’t address in this post.)

Meanwhile: thorough, apolitical, nuanced and transparent reporting of trial results would help doctors, patients and the general public understand what information is available.

Finally, in the next month or so I will look back over the full, provocative and generally excellent list by Drs. Smith and Hillner, and see what holds hope for the future of cancer medicine. What’s clear is that the path ahead mandates clear thinking through some very tough clinical decisions.

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Considering Steve Jobs, Medical Diagnoses and Privacy

Yesterday morning I wrote a short post on CelebrityDiagnosis.com. By evening, news broke that Apple founder and CEO Steve Jobs resigned from his position, presumably for reasons of his health.

What’s public, by Jobs’ decision, is that he had a relatively good, typically slow-growing kind of malignancy in the pancreas, a neuroendocrine islet cell tumor. He informed Apple employees by email about his diagnosis in 2004, when he was 49 years old. Since then he’s had a liver transplant. Possible complications of that surgery, or the tumor itself, have led to considerable speculation. But little is known about the details of why he took medical leave in January and is stepping down now.

In a published letter to the Apple Board and Community, he wrote yesterday: “I have always said if there ever came a day when I could no longer meet my duties and expectations as Apple’s C.E.O., I would be the first to let you know. Unfortunately, that day has come.”

The letter was “short and classy,” in David Pogue’s words, and I agree. I respect Jobs’ decision to keep the details of his medical condition private. That’s the thing – and where this is post is heading.

When public figures are open about their illnesses, it can be helpful, instructive and even necessary. For example, if a political figure, say Fidel Castro or Hugo Chavez or Dick Cheney, with considerable power develops a cancer or has a stroke or a heart attack or some other serious medical problem, the citizens have the right to know that the condition of the person they rely on has changed.

Sometimes it’s instructive to learn about famous people’s medical stories, as is illustrated in Barron Lerner’s book, When Illness Goes Public: Celebrity Patients and How We Look at Medicine. Openness about breast cancer by women like Happy Rockefeller, Rose Kushner and more recently Elizabeth Edwards (to name a few among many) have helped women move forward, from being ashamed of having BC to understanding about what it’s like to live with the disease. They helped other women to understand this disease, through their generosity of personal stories and experience.

The problem is that in our culture there’s so much openness about medical conditions, individuals may feel compelled to tell what’s happening if they have cancer or a recurrence or some other unfortunate medical event. But not everyone wants to do so, nor should they feel obliged.

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FDA Approves Adcetris for Refractory Hodgkin’s Disease and a Rare T-Cell Lymphoma

Late Friday afternoon, the FDA announced its approval, upon accelerated review, of a new drug, Adcetris (brentuximab) for patients with Hodgkin’s lymphoma that has relapsed after bone marrow transplant and for some patients with T-cell anaplastic large cell lymphoma (ALCL).Hodgkin's Disease pathology image shows classic "Reed-Sternberg" cell in center, W-C image

This interests me for a lot of reasons, among them that I used to work in the field of lymphoma immunology and spent some time in my life studying molecules like CD30, the protein to which the new antibody binds.

First, a mini-primer on the disease and numbers of patients involved:

Lymphomas are almost always tumors of lymphocytes, usually of T or B-cell type. In adults, around 80% of cases derive from malignant B lymphocytes; T-cell lymphomas form a varied minority. Approximately 66,000 people receive a diagnosis of non-Hodgkin’s lymphoma (NHL) every year in the U.S.; if a third of the 13,000 or so T-cell tumors are ALCL, there would be just over 4,000 cases of T-ALCL per year, of which only a fraction would require aggressive treatment (see below).

There are nearly 9,000 cases of Hodgkin’s lymphoma (a related condition, usually of B cells) each year in the U.S. Only a small fraction of the Hodgkin’s cases undergo bone marrow transplant and, of those, a smaller percent would relapse and need further treatment.

T-cell ALCL is a rare lymphoma subtype in which malignant T-lymphocytes express proteins including CD30, a complex signaling molecule of the TNF receptor protein family. Clinicians generally classify the disease based on whether it predominantly affects the skin, in which case it tends to be indolent, or if it affects internal organs like the bone marrow, liver and brain, in which case it tends to be aggressive and be unresponsive to standard chemo regimens like CHOP. The T-cell form of ALCL is unlikely to respond to Rituxan, a monoclonal antibody that binds to CD20 on B-cells.

Pathologists classify ALCL based on whether or not the malignant cells have a chromosomal translocation or subtler mutation involving the ALK (anaplastic lymphoma tyrosine kinase) gene. Presumably ALK (anaplastic lymphoma kinase inhibitors) are and will be tested in ALCL tumors with ALK mutations. Meanwhile, patients with ALK+ or ALK- variants seek better treatment options.

The new drug is a specially-designed monoclonal antibody that’s conjugated to a toxin. It binds a receptor, CD30, that’s found at the surface of activated T cells, normal and malignant, and on the most definitive Hodgkin’s lymphoma cells, aka Reed Sternberg cells.

As is the case for many cancer drugs, how Adcetris works is not perfectly clear. Prescribing information from the drug’s manufacturer, Seattle Genetics, says the antibody would be given every 3 weeks by intravenous infusion “until a maximum of 16 cycles, disease progression or unacceptable toxicity.”

The drug was developed by Seattle Genetics (Seagen.com) in collaboration with Millennium Pharmaceuticals, a pharma giant subsumed by Japan’s Takeda company. There’s a lot of money at stake.

Today Ed Silverman at Pharmalot reports on the price of the new drug:

…Seattle Genetics disclosed that the annual cost for Adcetris, which the FDA approved late last week to combat Hodgkin’s disease and another rare lymphoma, will cost $13,500 per dose. In clinical trials, patients received an average of eight infusions, which works out to $108,000 a year, which Xconomy reports was in line with several Wall Street estimates.

He wonders about the cost, and whether it’s justified. My view is that the drug’s use in T-cell ALCL seems reasonable because those patients have so few options. As for using it as a “salvage” drug in Hodgkin’s patients who’ve already undergone bone marrow transplant, a costly and toxic procedure, I’m less confident.

“Early clinical data suggest that patients who received Adcetris for Hodgkin lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy,” said Richard Pazdur, M.D., in the late-Friday press release. Dr. Padzur heads the FDA’s Office of Oncology Drug Products.

According to the press release, Adcetris was tried in a single-arm (non-randomized) trial of 58 patients with systemic ALCL. The tumors shrank partially or completely in 86 percent of patients. Their responses lasted 12.6 months on average. So far there’s been no demonstrated benefit in survival.

The data to support the drug’s use in Hodgkin’s patients after transplant come from a single-arm study of 102 patients who relapsed after autologous bone marrow transplantation. According to the FDA,  73 percent had a complete or partial response that lasted 6.7 months, on average, upon receiving the experimental drug. Again, there’s no demonstrated survival benefit, just a response rate reported by the agency.

There are over a dozen trials listed with ClinicalTrials.gov for Brentuximab Vedotoxin (SGN-35).

Meanwhile, we await FDA Commissioner Dr. Hamburg’s decision for Avastin in women with metastatic breast cancer.

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Reducing Costs by Better Integration of Palliative Care in Cancer Treatment

We’re up to point 9 on the list – and nearing the end – on Bending the Cost Curve in Cancer Care from the May 26 NEJM. The suggestion from Drs. Smith and Hillner is that doctors better integrate palliative care into usual oncology care.

The authors start this important section well:

We can reduce patients’ fears of abandonment by means of better-integrated palliative care. This topic is fraught with misunderstanding given the references to “death panels” during the recent debate concerning health care legislation…

Here they’re on target: Some patients think, mistakenly, that inclusion of palliative care in their treatment means their doctors are throwing in the towel. I’ve known some oncologists who think the same, who perceive palliative care as a last resort.

The truth is that palliative care, which aims to relieve symptoms, can be implemented at any point in the treatment of disease.

The authors go on to provide data that cancer patients who receive palliative care live just as long, or longer, than those who don’t, and that their medical bills are lower. The issue I have here is their choice of emphasis on a published study of the Aetna Compassionate Care Program in which nurses identified patients for palliative care by administrative claims, “thus bypassing the oncologist.” Evidently this strategy led to a doubling of hospice referrals and other possibly good effects.

Besides that the cited study was authored by employees of an insurance company, which I find unpalatable, the concept of having nurses do the referrals deflects the issue: that oncologists talk about palliative care with their patients, directly. Relying on nurses to carry out these conversations would, understandably, contribute to a sense of abandonment, even if the nurses do the job perfectly. A critical role oncologists is to communicate about treatment care options, part of the cognitive work considered in point 8 of this discussion.

But the main idea, that doctors should integrate palliative care into their cancer patients’ treatment planning, earlier, and as a supplement – and not a replacement – for potentially curative or tumor-shrinking strategies, is right on.

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Big Melanoma News: FDA approves Vemurafenib (Zelboraf)

Vemurafenib (PLX4032) structure, NCBI image

This morning the FDA announced approval of Zelboraf (vemurafenib) for treatment of some patients advanced melanoma. This is the second drug the agency has approved for this disease in recent months, after nearly two decades of a lack of new or effective therapies for melanoma.

Zelboraf is a pill. This small-molecule drug is thought to work by inhibiting an enzyme in malignant melanoma cells that have a specific BRAF mutation. A few months ago I wrote on this promising new drug, which goes by other names including PLX-0432.

The FDA also approved a companion test, cobas 4800 BRAF V600 Mutation Test, to check for the relevant mutation in patients’ tumors. Both the drug and the test are manufactured by Roche.

The other recently-approved melanoma drug, Yervoy (ipilimumab) is an antibody that’s given by intravenous infusion. This immune modulator, manufactured by Bristol-Meyers Squibb, works by a completely different mechanism: it blocks an immune system inhibitor, CTLA-4, and so “revs up” the body’s healthy immune cells in their capacity to destroy malignant melanoma cells.

Both new drugs are costly. A clinical trial, to test how the two drugs might work together in patients with the relevant BRAF mutation, should open for enrollment in September.

H/T to Sally Church @maverickny‘s early post on Pharma Strategy Blog.

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Notes on Kris Carr and Crazy Sexy Cancer

I’m half-tempted to put down yesterday’s new NYT Magazine feature on crazy sexy cancer goddess Kris Carr. Her blog was one of the first I found when I started ML, and it was the most popular link on my fledgling site until I pulled it, fearful of somehow sponsoring a too-alternative oncology perspective.

But I give Carr credit, sincerely: Crazy Sexy Cancer is a lot more appealing a title than, say, Medical Lessons. I’d read CSC, for sure, if I had a new diagnosis or, maybe, if I were alone and bored or suffering from a condition like chronic fatigue syndrome or insomnia and hadn’t gone to med school. Even for people who really have cancer, letting loose and being attractive sounds, well, like a lot of fun.

Kris Carr has played her C-card like a Queen of Diamonds. You go, girl!

So this morning I pulled a hard-cover edition of Cancer: Principles and Practice of Oncology, 7th Edition (2005; Lippincott, Williams & Wilkins; edited by DeVita, Hellman and Rosenberg) off my shelf and looked up Carr’s stated disease, epithelioid hemangioendothelioma. Being the old-fashioned woman that I am, I read about EH* in print. Only then did I discover a handy, unopened CD housed inside the cover of the “oncology bible,” as we used to call this text.

the editors, 'Cancer: Principles and Practice of Oncology,' Lippincott

DeVita and his colleagues classified this condition as a vascular tumor in a chapter on sarcomas, in a section on tumors that develop in smooth muscle. Now, at risk of boring my readers with the medical “scoop” on this strange and sometimes benign-behaving sarcoma variant:

As its name implies, epithelioid hemangioendothelioma is an angiocentric vascular tumor with metastatic potential…These lesions may appear as a solitary, slightly painful mass in either superficial or deep soft tissue. Metastases to lung, regional lymph nodes, liver, and bone are reported. Another pattern is that of a diffuse bronchoalveolar infiltrate or multiple small pulmonary nodules. This entity has also been called IBVAT…can also arise in the liver, often presenting as an incidental finding or as part of a workup for mild elevation of liver enzymes or vague abdominal pain. Multiple liver nodules are the rule. Although these lesions can metastasize, they usually run an indolent course. Liver transplantation has been performed…

This sounds scary, sure, but the bottom line is that this tumor falls into unchartered oncology territory because they’re so rare. As reported in the Times piece there are only 40-80 cases per year in the U.S. A reference in the textbook, above, leads to a 1989 report in the American Journal of Surgical Pathology. In that study of 10 cases, the authors describe an unpredictable course for the disease.

As told by Mireille Silcoff in the magazine, EHE comes roughly in two forms: one’s aggressive and one’s not. So what the oncologist at Dana Farber suggested – that she go about her life, and “let the cancer make the first move” – was a reasonable strategy, one that allowed them (patient and doctor) to find out, over time, what would be the nature of her particular EHE.

Carr lucked out: She has the “good EH” as Larry David might say. So far, at least, she’s enjoyed a  productive, enterprising  life with cancer. From the Times:

She was given the diagnosis in 2003 and rose to prominence with a 2007 documentary called “Crazy Sexy Cancer.” She subsequently wrote two successful books— “Crazy Sexy Cancer Tips” and “Crazy Sexy Cancer Survivor” — about her peppy, pop-spiritual approach to her disease, and she soon became what she sometimes describes as a “cancerlebrity” or, at other times, a “cancer cowgirl.”

Now she has a blossoming business. At the cafe, she laid it all out while sipping a coconut-vanilla chai with soy. Her blog postings are being syndicated, she has pending sponsorship contracts, her weekend workshops are thriving and she has provided one-on-one coaching sessions on Skype ($250 for 90 minutes). She also just bought a farm — 16 acres complete with two houses, a barn, a meadow and a forest…

Am I jealous? Sure, maybe, some…But I’d be hopeless on a farm.

Besides, she hasn’t received chemo, had limb-removing cancer surgery, undergone early menopause…She looks fabulous! And with that kind of cancer, maybe so would you.

The issue is that Karr runs a well-connected wellness enterprise. She sells a way of life, David Servan-Schreiber style, with the message that you can beat cancer and be well if you nourish your body and mind with the likes of 21-day cleansing diets, juiced Whole Foods and meditation-enhancing mala bead jewelry.

The danger is that readers and customers/followers may believe that her current well-being is due to her lifestyle choices. And that some people with the malignant form of EHE, whose emails she may not read, struggle with feelings of inadequacy and defeat.

So I’ve learned from Kris Carr: For one thing, I don’t think I ever saw a case of EH and she, through her story, persuaded me to look it up. Second, she’s a smart business woman, who’s turned her life around upon a cancer diagnosis. Third, (am undecided, ideas?)

And I’m taking careful notes. Let’s leave it with that, for now.

*This author prefers to call epithelioid hemangioendothelioma EH, but most sources use EHE, so I’ll abbreviate as do the sources or use my own style, accordingly.

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News on an Unusual Cancer Treatment by Heat in Surgery (Hipec)

There’s so much weird and exciting cancer news this week, it’s hard to keep up!

Double-kudos to Andrew Pollack on his front-page and careful coverage in the New York Times of the hyperthermic intraperitoneal chemotherapy (Hipec) technique that’s being used at some name-brand health care facilities to treat colon cancer.

First, he spares no detail in the Times describing the seemingly primitive, crude method:

….For hours on a recent morning at the University of California, San Diego, Dr. Andrew Lowy painstakingly performed the therapy on a patient.

After slicing the man’s belly wide open, he thrust his gloved hands deep inside, and examined various organs, looking for tumors. He then lifted the small intestine out of the body to sift it through his fingers…

….After about two hours of poking and cutting, Dr. Lowy began the so-called shake and bake. The machine pumped heated chemotherapy directly into the abdominal cavity for 90 minutes while nurses gently jiggled the man’s bloated belly to disperse the drug to every nook and cranny.

As a patient, I have to wonder, who’d sign up for this? And yet it seems they can’t complete a good randomized trial, for patients fear they’ll get the regular treatments only, without the Hipec. As an oncologist, I have to think, how can they possibly do a randomized clinical trial for this sort of method; the results would vary, enormously, from surgeon to surgeon, and from patient to patient – depending on the tumor load and responsiveness to heat, besides all the other tumor variables, even if the Hipec did help a patient or a few.

Pollack supplements the lead story with a shorter piece on hipectreatment.com, a website that obviously promotes the treatment but doesn’t reveal industry ties. According to his article, a competing site, HipecDoctor.com, lists doctors who do it (Hipec), but only includes those who use the site’s sponsoring company’s equipment.

At times like this, Nixon’s “war on cancer” takes on new meaning.

The business of oncology gets messy, on-line and in real patients’ guts. If you ask me, the Hipec approach might be labeled “alternative.” It’s certainly unconventional.

FDA, how do you classify this stuff?

HIPEC Surgery Featured on Grey’s Anatomy (KXLY news clip)

Hard not to contrast the Hipec news with the neatly-designed, high-tech and scientifically-detailed approach published yesterday in the NEJM for treatment of patients with chronic lymphocytic leukemia. That limited but fascinating report, of intense interest to cancer immunologists and gene therapists, serves mainly as proof of principle.

To find out more on Hipec, I intend to watch the segment of Grey’s Anatomy (see one of many related news clip here, scroll down) which may have popularized – and increased demand – for this procedure among desperate patients.

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Reducing Cancer Care Costs: The Value of Physicians’ Cognitive Work

We’ve reached what may be my favorite of the proposed ways to reduce cancer care costs, published in the NEJM by Drs. Smith and Hillner. Idea Number 8 is to realign compensation to value cognitive services, rather than chemotherapy, more highly.

What the authors are saying is that we’d save money if oncologists were paid more for thinking and communicating, relative to their compensation for giving chemotherapy. They write:

Medicare data have clearly shown that some oncologists choose chemotherapy in order to maximize income for their practice.<46,47> A system in which over half the profits in oncology are from drug sales is unsustainable.

They suggest that physicians’ compensation should go up, relatively, for time spent

  • referring patients for participation in clinical trials;
  • discussing orders for life-sustaining treatments;
  • considering advance medical directives;
  • talking about prognosis in family conferences.

I couldn’t agree more.

Take the clinical trials example. In my experience enrolling patients in clinical trials, it was a lot of work if you (the oncologist) wanted to do it properly: You’d have to read through the entire protocol; identify any potential conflicts of interest, look up any other protocols for which the patient might be eligible and (ideally) offer that as well, take the time to explain that it’s fine for the patient to not enroll – that there’s “no pressure” (subject of a future post: when patients feel that they should enroll in their doctor’s trial), answer all of the patient’s and a family member or friend’s questions about it, process the paperwork carefully…

And I’d add to the authors’ suggestions for compensation-worthy time spent:

  • going over pathology results, carefully and with an appropriate expert (a pathologist), and discussing the findings with the patient or designated proxy;
  • reviewing radiology images with appropriate specialists (x-rays, CTs, MRIs… comparing each with the previous studies) and sharing the results, as above;
  • checking blood work; abnormalities can be subtle; trends not obvious if results aren’t charted over time;
  • discussing the patient’s condition, periodically, with other doctors such as the internist (or pediatrician), cardiologist, pulmonologist, surgeon, etc.
  • researching relevant published studies and case reports for puzzling clinical situations (using Google, Medline, a real library, maybe calling an expert at another medical center…)
  • communicating with patient about the condition, more generally (not only about end-of-life issues) – such as explaining  a tumor’s known or unknown causes, treatment options, genetic and other implications of a cancer diagnosis.

Bottom line:

When oncologists earn more money by prescribing treatments like chemotherapy, there’s a conflict of interest and a tendency to give more treatment. If oncologists’ salaries were set based on a case load, or time spent taking care of patients that includes cognitive services – thinking and communicating – patients would get better care and less unwanted treatment.

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Breast Cancer Avastin Update

This afternoon Ed Silverman of Pharmalot reports that Roche has proposed a compromise to the FDA over Avastin’s use in women with metastatic breast cancer. The drug would be approved for use only in combination with paclitaxel (Taxol), for which the data are strongest, and with special warnings.

He writes:

The deal includes revised labeling in which Avastin would be recommended only for patients displaying “aggressive disease” and who have the fewest treatment options. Roche also suggests a Risk Evaluation and Mitigation Strategy, or REMS, as well as a Medication Guide.

This sounds like a reasonable solution. As I have considered elsewhere, the FDA commissioner’s decision is pending.

——

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Implications of the Oncology Drug Shortage

Today’s New York Times features an op-ed by Dr. Ezekiel Emanuel, on the oncology drug shortage. It’s a serious problem that’s had too-little attention in the press:

Of the 34 generic cancer drugs on the market, as of this month, 14 were in short supply. They include drugs that are the mainstay of treatment regimens used to cure leukemia, lymphoma and testicular cancer.

Emanuel considers that these cancer drug shortages have led to what amounts to an accidental rationing of cancer meds. Some desperate and/or influential patients (or doctors or hospitals) get their planned chemo and the rest, well, don’t.

Unfortunately, what’s behind this harmful mess is neither a dearth of ingredients nor unsolvable problems at most of the manufacturing plants. Rather, the missing chemotherapies are mainly old and inexpensive, beyond their patent protection, i.e. they’re not so profitable, and not high-priority.

Emanuel proposes that the prices of old oncology meds – drugs that can cost as little as $3 per dose – be raised so that the companies will make it their business to provide them. This seems like a reasonable idea, although I find it a bit too compromising. Why should we raise the costs of any medications above what’s necessary for their manufacture and distribution?

The underlying problem is that we rely on a profit motive to deliver needed health care in the U.S. This kind of financial incentive, even if you find it morally acceptable, doesn’t seem to be working.

That’s why I favor scrapping the system – in which insurance companies siphon off some 30 percent or so of expenses, and pharmaceutical companies take another big cut – and giving patients the care they need, profits aside.

The health care reform bill of 2010 didn’t go far enough. Not even close.

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