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

By |April 10th, 2012

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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Oh, No Methotrexate!

By |February 13th, 2012

structure of MTX (PubChem; NCBI)

I was astonished to learn that methotrexate supplies are running short. This chemotherapy may soon be unavailable to patients who need it. And it’s not just kids with leukemia, as the Times story highlights effectively.

Methotrexate is an old, bread-and-butter cancer kind of drug, a basic ingredient in standard regimens for many tumor types. I’ve personally administered this medication to patients with breast cancer, lymphoma, leukemia, head and neck tumors, ovarian cancer, colon cancer and people whose tumor cells spread to the brain. Doctors prescribe this drug, also, in a few non-malignant conditions, like rheumatoid arthritis.

Methotrexate has been used in cancer wards for over 50 years. And like other beyond-patent meds, it’s become less profitable to manufacture MTX compared to much costlier new agents. Hard to perceive this shortage as anything but a tragedy – that the business of health care renders valuable, inexpensive drugs out of reach.

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Study Finds Wide Variation in Reoperation Rates after Lumpectomy for Breast Cancer

By |February 6th, 2012

The Feb 1 issue of JAMA includes a major report on the practice of lumpectomy in the U.S. The study examined what happened to 2,206 women at four medical centers who opted for breast-conserving surgery at the time of breast cancer diagnosis. The main finding was that after lumpectomy, nearly one in four women had another operation to remove cancerous cells in the breast. Among all the breast cancer patients who began with a lumpectomy, 8.5% wound up with a mastectomy.

These are staggeringly high rates of re-operation in women who opted for small procedures to begin with. Many of the women who had additional procedures did so for concern over having “clean margins” – that upon removal of a tumor, the edges of the specimen don’t reveal malignant cells. Re-excision for patients with negative margins varied by hospital; at one medical center the re-excision rate was 1.7%, at another it was 20.9%. Analysis by surgeon revealed huge variation, with re-excision rates ranging between 0 and 70%. The incidence of positive margins was 14%.

What further clouds the story is that among women who did have positive margins, meaning that cancerous cells were evident along the edge of the lump removed, nearly 15% didn’t have a second procedure. The big picture is that there was little pattern – or reason evident, at least at the collective level – for the surgeries and decisions to re-operate after lumpectomy for breast cancer.

The study, funded by the NIH, was sufficiently large to merit concern. It involved careful chart and pathology review of the specimens through a consortium of four medical centers around the country: the University of Vermont, Kaiser Permanente Colorado, Group Health in Washington State and the Marshfield Clinic in Wisconsin. And it reflects current practice; the surgeries took place between 2003 and 2008.

Lumpectomy is a very common procedure – and a significant issue, in terms of costs, and risks, and decisions women make every day upon receiving a new BC diagnosis. An estimated 60-70% of newly-diagnosed breast cancer patients choose breast-conserving surgery. So we’re talking about 160,000 or so lumpectomies per year in the U.S. (very approximate, ES: 2/3 of 240,000 new BC cases).  The variable results affect cosmetic outcome – the very reason many women choose lumpectomy to begin with and, potentially, the rate of BC recurrence.

The authors discuss: “Our finding…suggests that patients under similar clinical conditions are likely to undergo reexcision based on the treating surgeon and not just the clinical characteristics.” They offer possible explanations, including differences in surgical training, surgeons’ confidence in their operative techniques, how tumors are assessed in the operating room, and variation in how pathologists review specimens and “call” the margins positive or negative.

All of this meshes with my experience – knowing women who’ve had breast-conserving surgery and then got mixed information about the results and what to do next. You’d think lumpectomy would be a standard procedure by now, and that decisions about what to do after the procedure, surgically speaking (let alone decisions about chemo, hormonal treatments and radiation) would be straightforward in most cases.

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What is the Disease Control Rate in Oncology?

By |January 24th, 2012

Last week I came upon a new term in the cancer literature: the Disease Control Rate. The DCR refers to the total proportion of patients who demonstrate a response to treatment.

In oncology terms: The DCR is the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).

Another way of explaining it: Some people with cancer have measurable, growing tumors. For example, a man might have a sarcoma with multiple metastases in the lung that are evidently progressing. If the patient starts a new treatment and the lung mets don’t shrink but stop getting bigger, that might be considered a stabilizing effect from the therapy, and his response would be included in the DCR.

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Regorafenib, an Experimental Pill Tested in Colon and Rectal Cancer Patients, on Conference Agenda

By |January 18th, 2012

Tomorrow the American Society of Clinical Oncology* will host its 9th annual GI Cancers Symposium. Bloomberg and the LA Times have already reported findings of a paper, still in abstract form, to be presented on Saturday.

The drug of interest is regorafenib, a pill that loosely inhibits quite a few kinases – enzymes critical in cell signals that control growth of normal cells, tumors and blood vessels. The experimental med, manufactured by Bayer, is also known as BAY 73-4506. The new data emerge from an international, randomized Phase III trial that goes by a loaded acronym: CORRECT.

The study included 760 patients with advanced colon or rectal cancer whose tumor progressed after receiving standard treatments. Participants received either the study drug or BSC (best supportive care) and a placebo. According to the paper, BSC includes antibiotics, pain meds, radiation for bone mets, steroids and some other treatments. The median survival in patients who received the Regorafenib was 6.4 months, compared with 5.0 months in patients who got the placebo. This difference, of 1.4 months in the median, was statistically significant. The “disease control rate” – a term that warrants separate explanation – was 44% in the regorafenib group c/w 15% in the placebo group.

The most frequent high-grade toxicities reported so far include a skin reaction affecting patients’ hands and feet, fatigue, diarrhea, elevated bilirubin in the blood, and high blood pressure. (Question to ask the oncologist who’s presenting these data at the meeting – was the elevated bilirubin from liver damage or hemolysis? With all the $millions spent on this trial, surely someone’s followed up on that detail.)

The language of the report and investigators’ comments are reminiscent of some regarding Avastin for advanced breast cancer. According to a media release: “…a subset of patients in the trial have responded particularly well to regorafenib, continuing to have stable disease for a relatively long time; research is ongoing to find ways to identify these individuals.” There are no biomarkers known to check for Regorafenib responsiveness.

What’s odd is that, according to the abstract, # LBA385, all patients entered the study between May, 2010 and March, 2011. This means some subjects were evaluated for less than a year, and the longest observation period for any patient on the trial is 20 months. Seems early to draw meaningful conclusions about the long-term toxicity and possible benefits of a cancer drug, especially for tumor types, like colorectal cancer, that don’t generally grow fast (c/w a condition like acute leukemia).

The list of investigators’ disclosures regarding ties to industry is too long to post here. You can find them at the tail end of the release. The FDA has assigned Fast Track status to this drug, according to Bayer.

*I am an ASCO member.

—-

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Learning From the San Antonio Breast Cancer Symposium, At a Distance

By |December 8th, 2011

There’s a ton of BC and women’s health news this week. But yours truly is, among other things, not in San Antonio where is the 34th annual San Antonio Breast Cancer Symposium.

NTW, quite a few major news outlets are covering this business closely and carefully, as are some bloggers I know. Upon reading the news, I was simultaneously impressed by the number of new drugs for metastatic breast cancer that are being tried, and daunted upon realizing how difficult (read: IMPOSSIBLE) besides costly it’ll be to sort out these drugs used in so many combinations. Rather than recapitulating the data, some of which was published on-line this week in the NEJM, and most of which are still preliminary, I thought I’d just list some of the drugs being tested, and add a bit about how they’re administered and might work:

Entinostat is an oral histone deacetyalase (HDAC) inhibitor that’s not yet available in the US by any prescription off protocol.

Everolimus is a tablet (i.e. a pill) designed to inhibit an enzyme called mTOR. It’s sold for use in some cancers under the brand name Afinitor.

Exemestane is a tablet that reduces estrogen production. It’s an aromatase inhibitor sold as Aromasin. (This drug was approved by the FDA in 2005; it’s not quite so new, but is being tested in distinct settings, mainly in women with early-stage BC.)

Pertuzumab is a monoclonal antibody that binds Her2, in a distinct way from Herceptin.

Obviously this is but a partial list of drugs discussed at the meeting. Still, it’s heartening to this one oncologist to review even a short list of diverse new agents that might arrest the disease.

The history of the SABCS is interesting.  From the organization’s website:  the first meeting was held in November 11, 1978 during what’s said to have been “Breast Cancer Awareness Week.” The original conference’s sponsors included the Cancer Therapy and Research Center (CTRC, at UT San Antonio), the Texas Division of the ACS, the University of Texas Health Science Center at San Antonio (UTHSCSA) and the Bexar County Medical Society. Some 141 physicians and surgeons attended what’s described as one-day course.

It grew…

Now, the SABCS hosts a 5-day program with physicians, scientists, patients, advocates, reporters…from around the world. It’s jointly-sponsored by the CTRC and American Association for Cancer Research (AACR) and the Baylor College of Medicine.

The Alamo (WC image)

Next year, maybe I’ll go to the 35th annual event, and see what’s really happening in San Antonio.

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Final Word on Avastin, and Why We Need Better Physicians

By |November 18th, 2011

Today’s breaking breast cancer news is on Avastin. The FDA has just announced, formally, that it will rescind approval for the drug’s use in people with metastatic breast cancer. Commissioner Dr. Margaret Hamburg writes this her statement:

I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients, and those who support them, to ask hard questions and demand explanations concerning the drugs that are recommended to treat serious illnesses.

On this much I agree with Dr. Hamburg – that patients and others, including doctors who prescribe treatments to patients with likely incurable illnesses, and all medical conditions, for that matter, should ask hard questions.

Others have already, immediately expressed that the FDA did the right thing. Because they think the FDA’s decision was rational, and it was. Likely there’ll be an editorial in the paper I usually read, celebrating the victory of reason over anecdote. The WSJ, whose words tend to align more with business interests, will likely be critical. Opponents of health care reform will, inappropriately and mistakenly, use this as an example of rationing, which it isn’t.

The fact is that many, and possibly most, medical treatments are given in the absence of studies to justify their use. So you might ask, instead, why give chemotherapy to most stage IV cancer patients. Or why give it in the adjuvant setting? Apart from some tumors, like some kinds of lymphoma and leukemia, and common breast and testicular cancers, and a few others, when carefully measured the benefit is often slim.

What I think is that Avastin is a scapegoat of sorts, a costly drug not particularly worse than many others, nor better, and that helps a small minority of women with a lethal disease for reasons their doctors can’t predict or explain.

We experiment, on insurance and Medicare dollars, with so many costly treatments. Bone marrow transplants, at a cost of hundreds of thousands of dollars per patient, for example, are given to some with little formal proof of benefit for the approved indications. But there’s a lobby for these treatments. Support comes from hospitals profiting from transplant procedures and, more subtly, from academic physicians who’ve built careers in that field and write papers about their benefits, complications and management. I might cite other complex, costly and unproved examples in oncology, surgery and other fields of medicine, but that’s not the real point for today.

What I wonder is, ironically, because the data on Avastin were collected so carefully, that its lack of effectiveness over a population of women was better-documented than has been the lack of evidence for other drugs and regimens. Besides, there’s no group of hospitals and doctors whose profit and livelihood, respectively, depends on giving Avastin to just a few people with metastatic breast cancer. There was just Genentech, an easy big-Pharma target, and a few women, pleading for continued access to a drug that’s helped to keep them alive.

(I wonder, also, had those patients who testified been men, would their words have been taken more seriously?)

Meanwhile, doctors can keep giving Avastin to patients with other forms of cancer, for which its efficacy is not so different as you might think. Like any drug, this drug’s response varies from patient to patient for every tumor type that it might be given. And the physicians can still give Avastin, as the commissioner points out in her decision, to women who can pay for it, by circumstances of their particular insurance, or good fortune of wealth. But some of these women’s families will be hurt hard by this FDA decision. Most are in the 99%.

And so maybe what we really need are better doctors, not only in oncology, who would carefully monitor patients when they give any and every medical treatment and stop it if it’s not working, and continue only if it helps, and would communicate and obtain informed consent through meaningful discourse.

If we had that, we’d save a lot of money, and get better care.

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Visiting the Scar Project Exhibit

By |November 7th, 2011

On Friday I visited the Scar Project exhibit at Openhouse, on Mulberry Street just south of Spring. Photographer David Jay offers penetrating, large, wall-mounted images of young people with breast cancer.

The photos reveal women who’ve have had surgery, radiation, reconstruction or partial reconstruction of the breasts. Some are strikingly beautiful. Some appear confused, others confident. Some look right at you, defiant or maybe proud. Some, post-mastectomy, adopt frankly or strangely sexual postures. Others hide a breast, or turn away from the lens.

This collection is not for everyone. The photos of ravaged bodies of women with cancer might be upsetting, if not frankly disturbing, to some who look at them. Not everyone chooses to do so.

The women’s scars and expressions are telling. Though not representative, these images reflect wounds not often-shown in medical journals, or elsewhere.

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August Farewell: A Short Tale of a Peaceful Ending of Life

By |November 3rd, 2011

I began reading August Farewell on the seventh day of that summer month. The date coincides with the beginning of David Hallman’s narrative of his lover’s death two years prior, and memory of their decades-long relationship.

A book by a gay Canadian Christian man might seem remote to a woman like me, who’s married, Jewish and lives in New York City. But Hallman connects, effectively; his story sticks and might influence the near-death arrangements of any person living in our modern world.

Hallman recounts the death of a man, his partner William (Bill) Conklin, who’d lived for years with multiple sclerosis and its debilitating effects. In August, 2009 Conklin learned he had advanced pancreatic cancer. The story works through the author’s 16 daily notes on meetings with doctors, nurses and palliative care specialists, and visits with old friends and family.

The patient chose to die at home and his partner, Hallman, honored his wishes. Their story of calm, palliation and love at life’s end is heartening.

Why post this now? Because the book’s calmness, and message, lingers.

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Two Faces of Pancreatic Cancer

By |October 6th, 2011

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

By |September 6th, 2011

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

By |August 22nd, 2011

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

By |August 18th, 2011

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)

By |August 17th, 2011

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

By |August 12th, 2011

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

By |August 11th, 2011

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

By |August 8th, 2011

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

By |August 7th, 2011

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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On Reducing Cancer Care Costs by Resetting Expectations, and Hope

By |August 5th, 2011

Today we should move forward on the list published in the NEJM on Bending the Cost Curve in Cancer Care. We’re up to point 7 in our discussion, what’s 2nd in the authors’ proposed changes in attitudes and practice: “Both doctors and patients need to have more realistic expectations.”

This point follows closely from the previous, that doctors need to talk with patients earlier on end-of-life issues. But the central issue here is that most patients with cancer are unrealistic about their prognosis, and that oncologists do a terrible job in correcting their misperceptions:

…According to one recent study, most of the patients with lung cancer expected to live for more than 2 years even though the average length of survival is about 8 months.3

Resetting expectations will be difficult. Tools are available to help the oncologist provide truly informed consent by sharing anticipated response rates, chances of cure (always near zero for patients with metastatic solid tumors), and side effects…Many oncologists do not have these skills,43 so use of a decision aid may help…

What they’re describing amounts to Lake Wobegon effect, from the patient’s perspective, and that may be fair enough.

But I think these authors are letting oncologists off easy. Why it is that they lack “these skills,” i.e. what it takes to help patients face reality? It happens yesterday I was reading Dave deBronkart’s book, How to Laugh, Sing and Eat Like a Pig, on his experiences as a patient with metastatic kidney cancer, and he cites a terrific, pertinent excerpt in Dr. Jerome Groopman’s The Anatomy of Hope:

Hope, unlike optimism, is rooted in unalloyed reality. …Hope acknowledges the significant obstacles and deep pitfalls along the path. True hope has no room for delusion.

Clear-eyed, hope gives us the courage to confront our circumstances and the capacity to surmount them. For all my patients, hope, true hope, has proved as important as any medication.

Groopman’s point is that real hope rests in reality.

Going back to the NEJM piece –

I don’t think oncologists need (or better, should need) decision aids to help them reset patients’ unrealistic expectations. What they need is time, and thoughtfulness, and the capacity to be genuinely empathic.

If our health care system promoted trusting, and ideally longer, relationships of cancer patients with their physicians, patients would be less fearful of hearing the truth, and their doctors would be less afraid to speak honestly with them. This would reduce cancer care costs by lessening futile treatments, and would improve the quality of the patient-doctor relationships in oncology, besides the quality of care, in itself, and patients’ experiences as they near the end of life.

—–

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Reducing Cancer Care Costs: Oncologists Need to Get a Grip on Reality, and Talk about Dying

By |July 29th, 2011

We’ve reached the second half of our discussion on Bending the Cost Curve in Cancer Care. The authors of the NEJM paper, Drs. T. Smith and B. Hillner, go on to consider how doctors’ behavior influences costs in Changing Attitudes and Practice. Today’s point on the list: “Oncologists need to recognize that the costs of care are driven by what we do and what we do not do.”

In other words (theirs): “The first step is a frank acknowledgment that changes are needed.” A bit AA-ish, but fair enough –

The authors talk about needed, frank discussions between doctors and patients. They emphasize that oncologists/docs drive up costs and provide poorer care by failing to talk with patients about the possibility of death, end-of-life care, and transitions in the focus of care from curative intent to palliation.

They review published findings on the topic:

In a study at our institution of 75 hospitalized patients with cancer, the oncologist had initiated a discussion of advance directives with only 2 patients.31 In a prospective, multicenter study of 360 patients, only 37% of the patients and their families could recall having a discussion about impending death with the physician.32 Such a discussion is a prerequisite to good planning. Oncologists wait until symptoms appear or until they believe that nothing more can be done.33 In one study, at 2 months before their death, half the patients with metastatic lung cancer had not had a discussion with their doctors about hospice.34 This may explain why in a recent series the average length of stay in hospice for patients with lung cancer was 4 days.35

Although I have questions about the specific methods for some of these references, the bottom line is clear: Oncologists wait too long to talk with their patients about palliative or hospice care.

What they’re saying is that doctors need to get a grip on the problem (to overcome their denial and inability to talk about death), if they want to help patients come to terms with the inevitable. Doing so would save billions each year in the US, and would also spare patients from futile treatments and needless suffering.

I couldn’t agree more. It’s a potential win/win, if physicians think realistically about the situation and possible outcomes, and speak openly – and gently, no matter what, with their patients.

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