Crizotinib, An Experimental Drug for Some Lung Cancers and Other Tumors With Alk Mutations

ML is excited upon reading the latest New England Journal of Medicine (NEJM) which she still receives in print. Today’s issue includes four articles, if you count the accompanying editorial, on an experimental pill for treating some forms of lung cancer and other tumor types with distinct genetic profiles.

The new drug, called crizotinib, is manufactured by Pfizer and targets cellular enzymes including ALK (anaplastic lymphoma kinase). Sound like a mouthful? Well, it turns out that ALK acts up in some cases of non-small-cell lung cancer – an old-fashioned, catch-all oncology term that refers to most types of lung cancer in the U.S. that, literally, don’t comprise cells that look small when examined with a microscope. This tumor category, which affects nearly 200,000 people in the U.S. each year, includes three main subtypes: adenocarcinoma – the kind of lung cancer most common in non-smokers, squamous cell carcinoma and what’s called (seriously) “large cell” lung cancer.

In approximately 5% of non-small-cell lung cancers the malignant cells have a particular chromosomal defect that renders them vulnerable to crizotinib: the gene encoding ALK, on the short arm of human chromosome 2 (2p) is rearranged nearby the gene encoding EML-4 (echinoderm microtubule-associated protein like 4), such that an abnormally active, fusion protein is active in the tumor cells. This hybrid gene product, the result of a particular chromosomal abnormality, is implicated in tumor cell growth and proliferation. Some of these and other investigators have previously demonstrated that crizotinib inhibits ALK activity in cells in vitro and in some animal models.

OK, so in the first of the NEJM papers*, 31 authors (including 16 in Boston, at Harvard affiliated-medical institutions and 5 based at Pfizer, in La Jolla, CA),  report on the trial of 82 men and women with non-small-cell lung cancer who qualified for the study. All had “advanced” tumors, meaning tumors that couldn’t be removed surgically, and 94% had tried other treatments before starting crizotinib. Each enrolled patient had a chromosomal rearrangement, identified by a molecular FISH study, resulting in the EML-4-ALK fusion protein. After some initial phase I work to test tolerance to this new drug, the patients were prescribed 250 mg by mouth, twice daily.

The results were dramatic, as things go for clinical studies of advanced non-small-cell lung cancer: 57% of the subjects responded (partially in all but one apparent instance, meaning that the tumors shrank but didn’t disappear). In an additional 33% of patients enrolled, the disease stabilized (meaning that the tumors didn’t get significantly smaller, but stopped growing as they were before treatment). Upon 6 months of treatment, the probability of progression-free survival was estimated at 72%, but the median had not yet been reached.

According to the study authors, the drug was well-tolerated overall, and most of the patients elected to remain on treatment after completion of the planned protocol. Among the 82 patients, 34 reported “mild” visual disturbances, according to the authors: “the events were most frequently described as trails of light following objects moving relative to the observer, particularly noticed during changes in ambient lighting…” These were considered “Grade 1,” according to Table 2 in the paper. Grade 3 and 4 toxicities were few, and mainly included abnormal liver enzymes affecting 5 or 6% of the patients.

The second paper is a case report, astonishing firstly because there are 18 authors describing the drug’s activity in 2 patients, and secondly because of the interesting nature of the tumor described, a condition called inflammatory myofibroblastic tumor (IMT). I don’t think I’ve ever seen a case of this, either in real-life practice or in preparing for my oncology boards, so for now I’ll quote the paper and say that IMTs occur mainly in young people and consist of malignant myofibroblasts – cells that, when normal, usually form muscle and related soft tissue structures. The ALK gene is rearranged and abnormally expressed in about half of these tumors.

Summary of the second paper: the investigators tried crizotinib in 2 patients with difficult cases of chemo-refractory IMT. One, a 44 year old man with a distinct ALK abnormality who’d undergone extensive abdominal surgery and received multiple chemotherapies, responded fabulously. The other IMT patient, a 21 year old man without evidence for an ALK rearrangement, didn’t respond to the drug.

The third paper, by a Japanese group with a corresponding author based at Jichi Medical University in Tochigi, Japan, describes the development of two secondary, acquired and resistance-conferring mutations in ALK in one lung cancer patient who was taking crizotinib. Among other methods, they performed deep sequencing to check the ALK sequence in many of the patients’ cells, and then confirmed the presence of 2 (but not 3, as were found by this method) mutations using Sanger sequencing. They performed some neat PCR tricks to amplify DNA that was specific to the tumor’s EML4-ALK hybrid, and determined that the two de novo mutations within the tumor cells were mutually exclusive: the patient seems to have developed two resistant tumor clones while on treatment with the ALK inhibitor.

Finally there’s an editorial, by two molecular biologists, Drs. B. Hallberg and R. Palmer, based in Sweden’s Umeå University. This drug has a lot of potential, is the gist of it. ALK mutations don’t just occur in some lung tumors and IMTs, but also in some childhood tumors called neuroblastomas and, more than occasionally, in some anaplastic lymphomas.

I am aware, also, from the NCI’s website and by reading, including some of the above articles, that crizotinib has activity against some other kinases, including c-MET and other signaling receptor molecules, some of which are implicated in cancer growth.

I contacted Pfizer today, and a representative informed me by email that pricing for crizotinib has not yet been determined. I asked about FDA plans, and he wrote: “Pfizer plans to submit crizotinib (PF-02341066) data in the first half of next year to the U.S. Food and Drug Administration (FDA) for regulatory approval.”

Now, there are several ongoing clinical trials of this drug, some for patients with non-small-cell lung cancer and some for patients with other “ALK+” tumors, meaning cancers that bear a mutation in the ALK gene.

Why am I blogging about this drug, a pill, that works imperfectly in perhaps most of 5% of non-small-cell lung cancer patients and, maybe, in some other rare tumors? Because this is the future of oncology and, ultimately I think, will provide cost-effective medicine that’s based in evidence and science.

The key is that the investigators tried the experimental drug in lung cancer patients with a specific genetic profile, one that predicts a response to this agent. If, in 3 or 5 or 10 years we could sequence a patient’s tumor and check for specific mutations, we could give medications tailored to what they’ve got, and avoid treating them with drugs that are unlikely to work. This kind of approach should, if done properly, reduce the costs of cancer care, if the drugs are reasonably-priced.

How drugs like crizotinib could save money:

1. This drug is a pill; slash the costs of IVs, pumps, bags of saline, nurses to administer…

2. Don’t give it to patients without a relevant genetic mutation;

3. Monitor patients for resistance and stop giving drugs when they no longer help the individuals for whom their prescribed.

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Stem Cells, Breast Reconstruction and a Magazine Cover

The cover of the November print edition of Wired features large, unnatural-appearing cleavage. Inside and toward the back of the issue, a curious article ties together stem cells and the future of breast reconstruction. It got my attention.

Wired, November 2010 issue

The detailed and admittedly interesting piece, by Sharon Begley, describes what’s science or science fiction: first humans, such as some plastic surgeons, remove adipose tissue, a.k.a. fat, by a well-established cosmetic surgery procedure called liposuction, from a body part where there’s a fat surplus – such as the belly or backside; next, laboratory workers purify and grow what are said to be stem cells from that that fat; finally, they use a nifty, calibrated and expensive device to inject those fatty stem cells where women want, such as in a hole or dimpled breast where a tumor’s been removed.

The story starts, unfortunately and distractingly, with a portrait of a male, enterprising and PowerPoint presentation-giving CEO of a biotech company, Cytori Therapeutics. Toward the end of the article, the author provides stats to support the potential business. Ultimately, improved breast cancer survival means that greater numbers of women will live more years after a lumpectomy or mastectomy, she explains. The reconstruction market may expand further, still, because some women opt for prophylactic mastectomies upon positive genetic testing for a BRCA mutation. Others, without cancer or high risk, might simply want to use these adipose-derived stem cells for cosmetic breast augmentation. What’s clear, if nothing else, is that women’s breasts are perceived as a commodity.

In between the money elements of the discussion, there’s some cool science about adipose-derived stem cells, which according to the cited scientists are quite prevalent in fatty tissue and relatively easy to grow if you give them some blood to feed on in the lab. A putative advantage of the cells is that they draw blood vessels to the area of engraftment, which is a concern to this oncologist (me) and, evidently, to an FDA panel that has not yet approved of this innovative method of breast reconstruction in women who’ve had breast tumors.

I’m not convinced, at least from what’s reported in this Wired article, that the cells used in this process are true stem cells, based on the high numbers the scientists describe finding so readily, and in rich proportions, in human fat tissues. It could be, for example, that what they’re isolating are really primitive adipose cells that can, indeed blend into the breast tissue and even recruit blood vessels as described, but aren’t true, pluripotent stem cells – the kind that can form any kind of blood cell or heart cell or neuron. Perhaps stem cells just sound sexy, at least to investors.

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New NY State Law on Information for Women Undergoing Mastectomy

A few days ago, NY State Governor Paterson quietly signed a new public health law* on information and access to breast reconstructive surgery. From the details provided on my state’s Open Legislation website, it seems this took place on August 13.

The purpose of the new law is to assure that all women undergoing mastectomy in NY are told about reconstructive surgery options and that insurance will cover those additional procedures.

What’s curious are two things – first, why so little coverage of this event? It is end-of-summer, I suppose.

But maybe editors and people like me who are educated in medicine and read newspapers are out-of-touch with the fact that many women who have breast cancer – over 200,000 each year in the U.S. – still don’t really know about breast reconstruction during or after cancer treatment. In my community, people read books and ask multiple doctors in second and third opinion before deciding whether to undergo a trans-flap or have implants inserted and then, once electing for implants, attempt a careful review the not-so-current literature on silicone vs. saline…

The reality is that many women, particularly poor women without newspapers or internet access in their homes, don’t know about any of this. They don’t know their insurance covers pretty much all of these options, by law. Now they will, or should as of Jan 1, 2011. Good.

The other curiosity is that a Montefiore Medical Center-affiliated plastic and reconstructive surgeon is said to have authored this bill, which was sponsored by State Senator Ruth Hassell-Thompson. The doctor’s intentions were surely good; he advocated its passage based on the sad case of a single mom who, after undergoing mastectomy and seeing several physicians, still wasn’t aware that she might undergo breast reconstruction. Nonetheless, it’s not surprising that a plastic surgeon in the Bronx cares about this legislation.

There is a dark side to this, unfortunately. Even among the women with good insurance and purportedly top docs, the results of reconstructive breast surgery are sometimes devastating to the women who undergo these procedures. These are no boob-jobs, and there’s widespread misconception about that. So I hope the law, also, might eventually protect women from botched attempts at reconstruction, an under-reported problem that might also be newsworthy.

*addendum – first link above adjusted because the previous url, http://www.cnbc.com/id/38743477 is no longer available, ES 2/14/11

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Why Blog on OncotypeDx and BC Pathology?

A few days ago I wrote on a relatively new pathology tool called OncotypeDx. This device measures expression of 21 genes in tumor cells to establish the likelihood a cancer will recur. For women with early-stage, ER+ tumors that haven’t yet spread to the lymph nodes, the OncotypeDx results stratify patients into three groups – those having a low, intermediate or high risk for recurrence at 10 years.

As things stand, chemotherapy is routinely prescribed for most women with early-stage BC after initial treatment by mastectomy or lumpectomy and radiation. But the overall relapse rate is fairly low (around 15% at 5 years, higher over time depending on other factors) for women who take an anti-estrogen pill like tamoxifen. Chemo reduces the recurrence rate by approximately one third. The problem is that women and their doctors don’t know in advance who’s likely to benefit.

Here’s why this is important:

What happens now is that most women choose to undergo treatment even though it’s unlikely their cancer will come back. This – the problem of overtreatment – was one of the main concerns to emerge from the mammography screening debate.

The original OncotypeDx data, which have been considered here and elsewhere, support that most women with low recurrence scores are unlikely to benefit from chemo. So if women and their doctors could access the kind of information provided by OncotypeDx, at a cost of ~$3800 each, tens of thousands of women with BC and low risk scores might opt out of chemo treatments each year.

For example, if a woman’s recurrence score is less than 18, the likelihood of a relapse within 10 years is only 7%. Such a patient might happily and rationally choose not to take adjuvant chemotherapy.

I can’t even begin to think of how much money this might save, besides sparing so many women from the messy business of infusions, temporary or semi-permanent IV catheters, prophylactic or sometimes urgent antibiotics, Neulasta injections, anti-nausea drugs, cardiac tests and then some occasional deaths in treatment from infection, bleeding or, later on, from late effects on the heart or not-so-rare secondary malignancies like leukemia. And hairpieces; we could see a dramatic decline in women with scarves and wigs.

So why doesn’t every woman with eligible (ER+, node-negative) BC get an OncotypeDx readout, or some other modern pathology report, such as Mammaprint, that’s available and already FDA-approved? (OncotypeDx is just an example, really, of an advance in science that’s moving at a snail’s pace into the clinic.)

One issue, perhaps, is that it’s challenging for some doctors to learn about this test sufficiently that they’re comfortable with it. Quantitative RT-PCR, the method by which RNA is measured in the assay, wasn’t invented until around 1990, long after many practicing oncologists completed school. And as for the particular 21 genes measured – they’re unfamiliar to most physicians I know. Now, you might say that it doesn’t matter – if the device works, the doctor doesn’t have to understand the underlying technology. But a black box-like approach to clinical cancer decisions is far from ideal.

From the physician’s perspective, it may be easier, and perhaps legally safer, simply to prescribe the chemo – which she knows well and uses all the time – than to engage in a decision-making process using new methods and terms she doesn’t fully command.

Besides, there’s a conflict of interest: many oncologists, hospitals and infusion centers make money by giving infusions of chemotherapy. Identifying a large subset of patients who wouldn’t benefit from chemo may not be a priority for some clinicians. In a recent JCO paper, half of the oncologists’ initial recommendations for a combination of chemotherapy and hormonal treatments changed to hormonal treatment (without chemo) upon seeing the patients’ OncotypeDx scores.

An ongoing large, NIH-sponsored TailorRx trial involving 10,000 patients aims to clarify the potential benefit of this test. I’m concerned that by the time those results are available, with relapse rates and survival curves at 5 and 10-years, the technology in science and availability of new treatments may persuade doctors, then, to question the trial’s relevance. Meanwhile, hundreds of thousands of women will be treated off protocol, many without this sort of information, in a sort of blinded guessing game about the chances of recurrence and whether or not they should take chemo.

For now I hope that all women with newly-diagnosed BC, and their physicians, know about OncotypeDx and other tools, and their potential to inform decisions regarding chemotherapy.

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More News, and Considerations, on OncotypeDx

This week I’ve been reading about new developments in breast cancer (BC) pathology.

At one level, progress is remarkable. In the 20 years since I began my oncology fellowship, BC science has advanced to the point that doctors can distinguish among cancer subtypes and, in principle, stratify cases according to patterns of genes expressed within tumors. This sort of information – cancer cell profiling – might inform prognosis and influence treatment decisions that BC patients and their doctors, usually oncologists, make every day.

What disappoints is the slow pace by which this knowledge infiltrates the clinic. In practice, women and their physicians rarely have much more information on BC pathology than what was available two decades ago – the tumor size in its largest dimension (crudely measured in centimeters), whether it’s spread to the lymph nodes (and if so, how many nodes), the type of cancer (based on the cells’ appearance under a light microscope: infiltrating ductal, lobular carcinoma and other BC forms) and whether the cells express a few key molecules including estrogen receptors (ER).

In the past five years, more laboratories are offering data on Her2 in BC samples. This complex molecule, an epidermal growth factor receptor, normally transmits signals from a cell’s surface to the interior. Her2 expression dictates the BC subtype in some newer classifications of the disease and usually determines the cells’ responsiveness to Herceptin, a monoclonal antibody treatment. Still, there’s been some controversy, in part due to variation among lab facilities in the reproducibility of Her2 testing results.

The problem is this: if pathologists don’t provide accurate, valid results on Her2 expression in BC cells – which can be measured by various methods – it’s hard for women and their physicians to make sound decisions based on the molecule’s expression. And Her2 is just one of dozens of molecules that can be measured in BC. The reason it’s tested, for the most part, is to foster decisions on Herceptin treatment and also, perhaps to a lesser extent, to provide prognostic information.

What puzzles me is why so few use better, modern pathology and other decision tools. Technologies like Mammaprint, Adjuvant! and OncotypeDx have been available for years but aren’t used routinely in most clinical settings. So I thought I’d do some more research and, in future posts, will consider each of these and other, relevant technologies.

For today I’ll focus on OncotypeDx.  This test, manufactured by the Redwood City, California-based Genomics Health, assesses BC recurrence risk in cases that are ER+, node negative (see below). As cancer gene testing panels go, OncotypeDx is a baby, based on expression of just 21 genes by a two-decade old method called quantitative RT-PCR. The test intrigues me; I’ve posted on it once before.

No doubt, my interest in OncotypeDx is intensified by my personal history of BC. My case was exactly the sort of ER+, node-negative tumor for which OncotypeDx is intended; often I’ve wondered what would have been my tumor’s recurrence score (RS) and if knowing that would have affected my decision to undergo treatment with adjuvant chemotherapy.

Some background terms –

ER+ means that the cells express hormone receptors, for estrogen, at the surface;

Node negative means that the breast cancer has not spread to the lymph nodes, or glands, of the armpit. (Axilla is the medical term for armpit. Axillary lymph nodes are normal immune organs that drain fluid including potentially foreign particles from the breast, chests and nearby arm. The nodes can swell if there’s an infection to which the body reacts, if malignant cells infiltrate the gland and sometimes due to autoimmune diseases like lupus.)

So an ER+, node negative breast tumor is one in which the cancer cells are sufficiently differentiated, or mature, to produce and bear hormone receptors at their surfaces and in which the tumor cells haven’t yet migrated to the armpit (or at least haven’t done so at a level that can be detected by a pathologist).

Real-Time, Reverse Transcriptase (RT) – Polymerase Chain Reaction (PCR) is a standard method for amplifying tiny amounts of nucleic acids such that they can be measured and sequenced. Standard PCR usually amplifies DNA whereas in RT-PCR, RNA transcripts are converted to DNA before amplification in a machine. This method can assess the amount of RNA, or message for a particular gene, that’s expressed in a pathology sample.

Adjuvant therapy refers to additional, or extra, treatment that’s given after initial cancer surgery to reduce the chances of the tumor’s recurrence.

Back to OncotypeDx –

This pathology tool predicts the likelihood that ER+, node-negative BC tumors will come back within 10 years of a woman’s primary treatment (mastectomy, or lumpectomy with radiation) usually followed by tamoxifen. The assay measures each of 21 genes in a panel and, using those results, calculates a “recurrence score” (RS) between 1 and 100. The higher the RS, the more likely the cancer will re-emerge after treatment.

According to the Genomics Health website, the test measures RNA in BC tumor specimens for the following transcripts:

Groups of genes measured in OncotypeDx assay, according to the manufacturer
cell proliferation tumor invasiveness growth factor receptors hormone responsiveness other genes of interest reference** genes
Ki-67

STK15

Survivin*

Cyclin B1

MybL2

Stromelysin 3

Cathepsin L2

Grb7

Her2

ER

PR (progesterone receptor)

Bcl-2*

Scube2

GSTM1

CD68

BAG1

Beta actin

GAPDH

RPLPO

GUS

TFRC

*In my opinion, survivin and bcl-2 might be better classified distinctly; the products of these genes inhibit apoptosis (programmed cell death).

**These “housekeeping” genes are not of known significance in BC pathology. Rather, they serve as controls in the assay for the quality of the RNA sample, and for comparison to other measured genes.

The OncotypeDx results are reported by risk group, as follows:

Low risk (RS <18, the 10-year recurrence rate was 7% in NSABP study – see below)

Intermediate (RS 18 – 30, the 10-year recurrence rate was 14%, in same);

Higher risk (RS >31, the 10-year recurrence rate was 30%, in same).

The tool has been tested in multiple clinical trials for its capacity to predict BC recurrence after surgery and tamoxifen in women with ER+, node-negative tumors. The study most-cited, and from which the above statistics are drawn, was published in the New England Journal of Medicine in 2004, based on a retrospective analysis of 668 cases by Genomics Health in collaboration with investigators of the National Surgical Adjuvant Breast and Bowel Project (NSABP, a large, NIH-sponsored, multicenter cancer research effort).

OncotypeDx has been on the market since 2004. The cost of one assay runs near $3800, and most U.S. insurance plans including Medicare will cover it. Tumor samples, set in fixative, are sent to a single lab – a Genomic facility – that’s regulated according to the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The whole process takes 10-14 days. Still, the FDA has not approved the test for use as a decision-making tool.

Meanwhile, an NCI-sponsored trial called TAILORx will recruit and evaluate 10,000 women with ER+, node negative disease. Those investigators will determine, prospectively, if decisions based on OncotypeDx results can safely spare women with low RS the side effects and toxicity of chemotherapy without compromising their survival.

Why Oncotype and other new BC pathology tools matter –

In the U.S., the number of women who learn they have an ER+, node-negative BC approximates 100,000 per year. The question of adjuvant therapy – whether a woman should take tamoxifen or another hormonal agent and/or chemotherapy after surgery to reduce the risk of recurrent disease – is crucial.

If patients and their doctors could access more detailed molecular information about each case, they’d have a better sense of whether adjuvant treatment is likely to help in their particular situation. This approach would, potentially, spare many individuals with early-stage BC the costs, toxicity and hassle of unneeded chemotherapy. At the same time, it would help patients with small but riskier tumors by informing them that they have a high RS and thereby would more likely benefit from added therapy. Fewer women would receive chemotherapy, driving down costs, and the risks of additional treatment would be assumed only by those with a high likelihood of recurrence.

Some numbers here might help:

Overall, for women with ER+, node-negative tumors the chances of cancer recurring five years after primary treatment (mastectomy, or lumpectomy and radiation) followed by tamoxifen are around 15%. Over time that risk rises – BC can strike back after 10, 15 years or even later; the recurrence rate is said to approach 30% over time. In general, a basic chemotherapy regimen – something like CMF – cyclophosphamide (Cytoxan), methotrexate and 5-fluorouracil (5FU) reduces the probability of recurrence by about a third.

So if 100 women with node-negative tumors have to decide whether to take chemotherapy after surgery +/- radiation, or not, without a tool like OncotypeDx or another modern pathology test, they’re making those decisions based on very crude approximations of their odds. Because they don’t know whose tumors will recur, most if not all of their oncologists will recommend chemotherapy. And most women do choose to undergo the extra treatment because they’re afraid that, otherwise, there’s a greater chance the cancer will come back.

This is exactly the situation I faced in November, 2002, when I had an ER+, node negative, 1.5 cm tumor. Then, I reasoned that BC tends to be more aggressive in younger women. With hopefully more decades ahead in my life – more time, in effect, for the disease to recur – an 85% disease-free rate at 5 years wasn’t good enough. So I went for the chemo and upped my chances to the 90% range. Not a big difference in the stats, but I wanted to position myself on the upper branch of that Kaplan-Meier curve. Now, had I known my recurrence score based on the pattern of gene expression in the tumor cells, that information would have been useful. But it wasn’t an option then and, unfortunately, it’s still rarely available to most women who are undergoing treatment for BC in 2010.

The slow pace of progress, science in hand, is kind-of shocking.

So what’s new with OncotypeDx?

Two months ago, I reviewed a small study published in the ACS Cancer journal on the experiences of most of 100 women with newly-diagnosed breast cancer whose oncologists used the OncotypeDx assay to evaluate their cases. In that, two-thirds of the women reported they “understood a large amount or all” of what the doctors told them about the results and nearly all said they would undergo the test if they had to decide again.

In its April 1 issue the Journal of Clinical Oncology (JCO) published two relevant reports and an editorial. These papers support that OncotypeDx offers useful information to women with early-stage breast cancer and that it can assist patients and doctors in care decisions, in some cases providing support for them to choose a chemotherapy-free treatment regimen.

One study, a “Prospective Multicenter Study of the Impact of the 21-Gene Recurrence Score Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection” by Dr. Shelly Lo and colleagues, followed the analysis and prescribing patterns of 17 medical oncologists at 3 diverse academic medical centers and one community hospital. Genomic Health, provided free OncotypeDx kits and testing at their central lab for all 93 patients with ER+, node-negative BC who enrolled in the trial.

The mean age of the women was 55 years (range 35 – 77). The oncologists were asked to state their treatment preferences (hormonal treatment with or without chemo) before and after receiving the OncotypeDx results for their patients. What happened was this:

Before seeing the OncotypeDx results, the oncologists recommended chemo and hormonal therapy (CHT) to 42 of the 89 women for whom the study was completed. In 20 of those 42 cases (22% of the total, and nearly half of those women who were to receive chemo) the doctors changed their recommendation from CHT to HT (hormones only) upon reviewing the OncotypeDx report. In 8 cases, the oncologists switched their recommendation to include chemotherapy. In total, the OncotypeDx results influenced the oncologists’ preferences in 31% of the cases – nearly a third.

As for the patients – 74 of the 89 (83%) said the OncotypeDx results influenced their treatment decision. The assay report persuaded 9 patients in the group to opt for a less aggressive (chemo-free) approach. The majority (78 women, 95% of those responding) said they were glad they used the OncotypeDx assay. According to the paper, many patients felt reassured by the assay findings and benefited from a diminished perceived risk of recurrence (less worry, in effect).

The upshot is that the OncotypeDx assay – which costs around $3800 per evaluation – led to significantly fewer women with early-stage breast tumors getting chemotherapy in this trial of 89 patients. The doctors were more confident in their decisions to not give chemotherapy in cases with low RS and, overwhelmingly, the women felt glad about the decision-making process.

In the second JCO study in the April 1 issue, the number of patients evaluated was much greater – over a thousand. But this was a more complicated analysis in which the investigators applied OncotypeDx to old tumor samples and then, upon reviewing those cases in some well-documented randomized trials, examined how the cases fared in relation to the RS. What they found was that OncotypeDx score predicted the likelihood of loco-regional recurrence (LRR) in women who had node-negative, ER+ disease.

Bottom line –

The OncotypeDx tool has been on the market for 6 years. It has, in multiple and well-done studies, identified patterns of BC gene expression that accurately predict the likelihood of recurrence in women with early-stage, ER+, node-negative tumors. This should, in principle, reduce administration of chemotherapy – along with its attendant risks, costs and side effects – to women whose tumors are unlikely to relapse. Recent trials show that doctors find the results useful and that patients find it helpful in their decisions.

I can’t know for sure why the tool’s not used more often. But I have some concerns:

1. It takes time for doctors – even knowledgeable oncologists – to learn about this device, to know how it differs from other BC pathology tests like Mammaprint and decision tools (like Adjuvant!) and then it takes even more time for those physicians to discuss the results with their patients.

From the perspective of a physician sitting behind her desk or at a table with a newly-diagnosed BC patient, saying “this is what I think, you need treatment X” may be a lot easier than “well, let’s go over these OncotypeDx results…”

2. If the OncotypeDx report does indeed identify large subgroups of early-stage breast cancer patients who don’t need chemotherapy, the use of this test would reduce the number of patients who get chemotherapy. Oncologists, infusion centers and others generate income by prescribing chemotherapy. So there’s a potential conflict of interest.

3. Perhaps some physicians fear lawsuits for not giving chemotherapy to women who, without the OncotypeDx results, would receive it.

4. Some doctors might not recommend OncotypeDx because they don’t really understand the test, its merits and limitations.

5. Maybe OncotypeDx isn’t the best of the new BC adjuvant therapy decision tools. For this reason, among others, I will consider some of the other methods available in future posts.

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Other, Oral Targeted Cancer Treatments

Some of you may be wondering why I’m so fixated on oral, targeted therapies for cancer. In my last post I provided some information on nine cancer drugs aimed at cellular enzymes, or kinases.

I’m encouraged, first, by the rapidity of these drugs’ emergence: ten years ago, none of the kinase-blocking drugs were available except for a few in experimental trials; most received FDA approval only in the past five years. These are very new agents indeed.

Why I’m enthusiastic – I anticipate that within a few years from now, cancer patients will take “medication cocktails” for their tumors, much in the way people living with HIV use drug combinations to fend off infection.  Cancer will, in many circumstances now deemed incurable, be managed instead as a chronic disease.

Now I can complete my assignment – a list of current, oral FDA-approved targeted cancer therapies. As indicated previously, I’m not including hormonal treatments in this list. I considered oral drugs targeting kinases in the last post.

I should emphasize that I’m neither recommending nor advocating any particular drugs. Rather, my point is to demonstrate the evolution of the field, that so many new and varied types of cancer pills are available. I think this is the start of a new era in oncology with expanded treatment options for people with all kinds of malignancy.

Part II of FDA-approved Oral Targeted Treatments for Cancer (see also part I – on oral kinase inhibitors)

1. Zolinza (vorinostat) is FDA-approved for use in a few forms of lymphoma that are cutaneous T cell lymphoma (CTCL). These are non-Hodgkin’s lymphomas in which the malignant cells are T-lymphocytes infiltrating the skin.

How this agent works is by inhibiting histone deacetyalases. These enzymes act in the cell’s nucleus, or center, where lies the DNA strung out along chromosomes. It removes acetyl groups, small chemical structures, from histone proteins. The genetic material normally wraps around the histones, and the presence or absence of acetyl groups on histones affects how genes are turned on or off. (Merck, October 2006).

2. Targretin (bexarotene) comes in capsule and in gel forms. It’s a retinoid, a Vitamin A-like compound that binds retinoid X receptors. These receptors regulate gene expression in normal and malignant cells. The drug is FDA-approved for use in CTCL. (Ligand, now Eisai, December 1999).

3. Vesanoid (tretinoin) is a retinoid that binds retinoic acid receptors. This drug is approved by the FDA as part of the treatment regimen for a particular form of leukemia called acute promyelocytic leukemia (APL). The drug targets a retinoic acid receptor that’s abnormally produced in the malignant cells due to a disease-defining chromosomal switch involving the retinoic acid receptor alpha (Roche, and generic, 1995)

This list is derived, in part, from information on the National Cancer Institute website on targeted cancer therapies, supplemented by other public-access resources on the relevant drugs and molecules as I’ve indicated with relevant links.

Some comments:

In this review, I note that some drugs that are not conceptually distinct from conventional chemotherapy or hormonal treatment appear to be marketed as “targeted” cancer treatment. My concern is that some companies are using this term, which implies a scalpel-like effectiveness and selectivity, to sell drugs to patients and oncologists (who may not all be up on their kinases) regardless of the drugs’ real specificity or lack thereof.

Given that all cancer drugs are designed, in principle, to kill malignant cells without killing the person who has cancer, we might consider all anti-tumor drugs as “targeted therapy.” But I don’t think that would be reasonable or helpful to patients and physicians who are trying to distinguish among treatment options.

In my opinion, the “targeted” term should apply only to drugs that impede troublesome molecules that act up particularly in the malignant cells, such as the bcr-abl tyrosine kinase mentioned in the last post, or the altered retinoic acid receptor that’s implicated in APL, as considered above.

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Some Targeted Therapies for Cancer Come as Pills

This post, on FDA-approved small-molecule targeted therapies for cancer, seems like a homework assignment of sorts. But really I found it a useful exercise and hope some readers might find it so, too. In searching the Web, I found remarkably little on this that’s public-domain, comprehensive and organized. In fact, there seems to be a lot of confusion about what these drugs are and how these differ from conventional, cytotoxic chemotherapies.

Some historical perspective:

Before 1970, few people received chemotherapy. Even with a cancer diagnosis, most treatments were surgical and radiation-based. A few older agents, chemotherapy pills such as chlorambucil and melphalan were given by mouth. From 1970 until 2000 (more or less), the thrust of most new cancer treatments involved stronger and sometimes more effective combination chemotherapy regimens. Almost all of those new treatments were given by intravenous (IV).

One point here that’s relevant to health care reform and the current debate on physician payments is that as things stand, oncologists and medical centers make money by giving IV infusions. Each treatment is billed as a procedure, apart from the cost of the medication in itself. So if patients can take a drug without a catheter, it might be less costly – there’s no nurse to hire, no catheter to purchase and insert and there’s no billing for an infusion per se.

And there’s less cost to the patient in terms of hassle and some untoward effects of IV treatment. With oral drugs (capsules, pills or tablets – anything taken by mouth) there’s no need to go to the doctor’s office or medical center every week or every other week, or even daily as is prescribed for some chemo regimens. There’s no need to have one’s arms shot up or a permanent, dangling catheter inserted. There’s no attendant risk for infection from an IV or semi-permanent catheter.

Reality check: most effective cancer drugs are not available in pill form, and for the most part these targeted treatments are in their infancy. But their number is expanding, so much so that most of the cancer pills I’m about to list have been approved only in the past five years.

Take further note: these are toxic drugs. Targeted therapies are designed, in principle, to kill malignant cells while leaving normal, healthy cells alone. Unfortunately, the effects of the medications listed below are broader than would be ideal. In general, these pills take aim at molecules that are over-active in cancer cells. But most of the affected enzymes are present in regular, healthy cells, too.

Here’s a list of small-molecule, oral drugs that target cancer cell enzymes and have received Food and Drug Administration approval prior to March 9, 2010, in order of approval:

1. Gleevec (imatinib, STI-571) was the first drug in this class to receive FDA approval. It counteracts an abnormal enzyme, a tyrosine kinase, that’s active in chronic myelogenous leukemia (CML) cells. The malignant tyrosine kinase, bcr-abl, arises in most cases from a chromosomal switch, called the Philadelphia Chromosome.

It turns out this drug works, also, against another tyrosine kinase, one related to a cell surface receptor protein called c-kit that’s mutated and activated in many Gastrointestinal Stromal Tumors (GIST). In 2002 the FDA approved use of Gleevec for GIST tumors in “c-kit+” tumors, meaning GIST cancers in which the c-kit receptor is mutated.

Since then the drug’s been approved for additional uses, only in some and quite specific circumstances, for adults with acute lymphoblastic leukemia (ALL) in which the malignant cells harbor the Philadelphia Chromosome (Ph+) and for some patients with other, mainly rare blood disorders in which particular genetic changes are established. (Novartis, May 2001)

2. Tarceva (erlotinib). This drug is also a tyrosine kinase inhibitor and is thought to act primarily by blocking growth signals of the Epidermal Growth Factor Receptor (EGFR). The drug was initially approved for use in some patients with non-small cell lung cancer and, more recently, for patients with pancreatic cancer. (Genentech, November 2004)

(Here I should mention Iressa (gefitinib) that was approved by the FDA early on for treatment of patients with advanced non-small lung cancer. Like Tarceva, Iressa has activity against EGFR-linked kinase activity and growth signals. The drug is no longer approved for most patients. AstraZeneca, 2003)

3. Sprycel (dasatinib). Like Gleevec, this targeted therapy blocks the bcr-abl tyrosine kinase activity in CML. The FDA approved this medication for CML patients whose disease progressed while on Gleevec (Gleevec-refractory CML) and for some adults with ALL in whom the malignant cells are Ph+. (Bristol-Myers Squibb, June 2006)

4. Sutent (sunitinib). Sutent is approved for use in metastatic kidney cancer and in GIST tumors that have progressed during treatment with Gleevec. It’s a fairly broad-acting tyrosine kinase inhibitor. (Pfizer, January 2006)

5. Tykerb (lapatinib). Tykerb is the only small-molecule drug that’s FDA-approved for use in some breast cancer cases. It blocks growth signals through Her2 (Her2/neu), a receptor tyrosine kinase that’s present on the surface of some breast cancer cells. The drug is approved for patients with metastatic breast cancer that’s Her2+ (meaning that the malignant cells display this molecule) and when it’s given in combination with Xeloda (capecitabine, an oral version of an otherwise conventional chemotherapy).

In January of 2010, the FDA granted accelerated approval of Tykerb in conjunction with Femara (letrozole, a hormonal therapy) in some patients with metastatic, Her2+ breast cancer in which the cells also express estrogen and/or progesterone receptors. (GlaxoSmithKline, March 2007)

6. Tasigna (nilotinib). This is the latest drug to tackle the bcr-abl tyrosine kinase activity in CML. It’s approved for adults with CML who have failed at least one regimen containing Gleevec. (Novartis, October 2007).

7. Nexavar (sorafenib). This therapy may not be targeted in the truest sense because its activity is so broad. It blocks receptor-linked tyrosine kinases such as those associated with Vascular Endothelial Growth Factor Receptor (VEGF-R) and Platelet Derived Growth Factor Receptor (PDGF-R). It inhibits other types of signaling enzymes inside cells, such as Raf-associated serine-threonine kinases.

The FDA has approved this drug for two groups of patients: those with advanced renal cell (kidney) cancer and those with liver tumors that can’t be removed by surgery.  (Bayer, November 2007)

8. Afinitor (everolimus) is in a slightly different class of drugs, in that it blocks mTOR (mammalian target of rapamycin, another sort of cellular enzyme). This drug is approved for use in patients with metastatic kidney cancer whose disease has progressed after Sutent and Nexavar. (Novartis, March 2009)

9. Votrient (pazopanib) blocks numerous tyrosine kinases and is the latest FDA-approved drug in this class. It’s approved for patients with advanced renal cell (kidney) cancer. (GlaxoSmithKline, October 2009)

Note to readers: other, oral targeted therapies are available that act by different sorts of mechanisms. I will cover those separately.

Several websites provide more information on so-called targeted therapies for cancer, including new intravenous treatments, monoclonal antibodies and some drugs that act by distinct mechanisms. Some of the sites I recommend for this topic include the National Cancer Institute and the American Society of Clinical Oncology’s Cancer.Net.

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Considering Targeted Therapies For Cancer

I first heard about STI-571 (Gleevec, a targeted cancer therapy) from a cab driver in New Orleans in 1999. “Some of the doctors told me there’s a new cure for leukemia,” he mentioned.

We were stuck in traffic somewhere between the airport and the now-unforgettable convention center. His prior fare, a group of physicians in town for the American Society of Hematology’s annual meeting, spoke highly of a promising new treatment. It seemed as if he wanted my opinion, to know if it were true. Indeed, Dr. Brian Druker gave a landmark plenary presentation on the effectiveness of STI-571 in patients with chronic myelogenous leukemia (CML) at the conference. I was aware of the study findings.

“Yes,” I said. “There is a new drug for leukemia.”

Since then, oncologists’ enthusiasm for targeted therapies – medications designed to fight cancer directly and specifically – has largely held. But the public’s enthusiasm is less apparent. Perhaps that’s because many people are unaware of these new drugs’ potential, or they’re put off by their hefty price tags.

Today Bloomberg News features a detailed and, I think, thoughtful story on the high cost of Sutent (sunitinib malate). This “miracle drug,” similar in many ways to Gleevec, typifies the problem of developing and providing new targeted therapies for patients with cancer. Sutent costs as much as $200 per pill, amounting to almost $50,000 per year for those who benefit. But the drug helps only a fraction of the patients for whom it’s prescribed.

So I thought I might review targeted cancer therapies, the costs-benefits issue being real and relevant. N.B.: addressing these drugs’ relative merits, effectiveness and side effects is beyond the scope of this blog. Rather, I’ll try to provide a simple framework for understanding these drugs, some information on the distinct types of new treatments and how these might work to fight cancer.

First, the framework: although many news articles consider targeted therapies together, I’d divide these in three main classes:

1. Enzyme Inhibitors. These drugs, most of which are available as pills, are designed to inhibit specific, abnormally-active signaling molecules in cancer cells. Gleevec was the first of this sort of therapy approved by the Food and Drug Administration.

2. Monoclonal antibodies. Antibodies are proteins that healthy immune cells, called B lymphocytes, generate in response to infection. Whether medicinal or native, these complex molecules circulate in the plasma component of the bloodstream. What matters to many patients is this: antibodies are given by infusion (intravenous, IV) or, rarely, by injection. Herceptin (trastuzumab) is a good example of a targeted, monoclonal antibody treatment for breast cancer.

3. Hormonal treatments. These, for the most part, target estrogen receptors in breast cancer. (I am not convinced that these are truly “targeted therapies,” but as the NCI website lists these as such, I’ll go with the flow. Femara (letrozole), a drug that reduces estrogen and other steroid levels, falls in this class.

In a forthcoming post I’ll review the small molecule-type targeted therapies for cancer that have been approved by the FDA. After that, the monoclonals. If I’m feeling brave, I may cover hormonal treatments for breast and prostate cancer.

As for traveling in New Orleans, I hope to get back there soon enough. If I do take a cab there, I wonder what news the driver will report.

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Today’s Press on Targeted Therapy for Cancer

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

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

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

Here’s some of what I learned:

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

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

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

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

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

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

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News on Aspirin After Breast Cancer

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

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

This is a phenomenal report in three respects:

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

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

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

About aspirin:

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

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

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

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

About the study:

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

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

About the findings:

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

Aspirin Use, Relative Risk for Death from Breast Cancer

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

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

Aspirin Use, Relative Risk of BC Recurrence.

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

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

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

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

Some details:

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

—–

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

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Health Care Costs, Communication and Informed Choices

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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A Visit With My Oncologist

Today I visited my oncologist for a checkup.

Waiting to see her, I sat in a floral fabric chair by a matching wood veneer coffee table strewn with worn magazines – Architectural Digest, Better Homes and Gardens and some old Time issues – I couldn’t help but think of how I was feeling seven years ago.

Then I was anxiously waiting to know my blood counts – the white cells, red cells and platelets – to see if they were sufficient for my scheduled chemotherapy.

That January, my white blood cells were so low that some doctors thought I should enter the hospital for IV antibiotics. (I declined.) My mouth was so full of sores I could hardly speak or eat. My hair was gone and I wore a strange wig. My right arm was broken (yes, I’m right-handed) so I couldn’t write or type. I was pale, weak with anemia and covered with bruises.

Chemo-brain, which I’d never learned about in med school, was just starting to set in. Before then, I’d always taken pride in keeping up with medical and science journals. But I could barely muster the energy to take a glance at those heavyweights. Even regular magazines appeared fuzzy, a scary symptom for an oncologist who knows too well that breast cancer cells can spread upstairs.

I wanted my next treatment. I wanted to get it over with, to put the breast cancer behind me.

After a while my oncologist stepped out into the waiting area and guided me to the hall by her office. “The cells are low,” she said. “We’ll have to wait another week, that’s all.”

I knew she was right. But a week seemed like a lifetime to me then.

I understood that giving chemotherapy suppresses the bone marrow, the body cavity where blood cells form. If my white cells dropped any lower, I’d be at serious risk for bacteria in the blood or invasive yeast in my mouth and throat. If the treatment reduced the red cell-forming elements in the marrow, I’d become more anemic. Already I was on a medication that affected the function of platelets, the blood-clotting cells. If the platelets fell further, I’d be at greater risk for bleeding.

I had no choice but to wait. So I did. The next week I got my treatment, and we were back on track, at least for a while.

Today, sitting in a similar chair, I calmly read the arts section of the newspaper and started working on the crossword. I’d tucked the New England Journal of Medicine into my bag, thinking I should read that, but it didn’t seem right. I wanted to remember what it’s like to be a patient who doesn’t know if she’ll make it through.

Several of my friends, mainly women, are affected now by cancer that’s spread. They go to see their oncologists regularly, and sit and wait for their blood counts, and sometimes get their treatments. Most hold undeniably upbeat, positive attitudes. But the reality is tough-going, day-to-day and month after month, with no easy end in sight.

How much easier it is to look back on a situation – a tumor – that was removed in an early stage. My cancer treatment wasn’t easy, but I don’t regret it for a second.

When my oncologist took me into her office today we chatted for a while and then she examined me.

“Come back next year,” she said.

In my medical storybook, it doesn’t get much better than that.

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How to Avoid Death in the ICU

Something I learned as a medical intern is that there are worse things than dying.

As I recall, it was sometime in April, 1988. I was putting a line in an old man with end-stage kidney disease, cancer (maybe), heart failure, bacteria in his blood and no consciousness. Prince was on the radio, loud, by his bedside. If you could call it that – the uncomfortable, curtained compartment didn’t seem like a good place for resting.

An attending physician, a smart guy I respected, approached me as I completed the procedure.

“It’s kind of like Dante’s seventh circle,” he noted.

Indeed. A clear, flexible tube drained greenish fluid from the man’s stomach through his nose. Gauze covered his eyes, just partially. His head, hands and feet swelled with fluid. A semi-opaque hard-plastic instrument linked the man’s trachea, through his paper-taped mouth, to a noisy breathing machine. His skin, barely covered by a stained hospital gown, was pale but blotchy from bleeding beneath. An arterial catheter inserted by his wrist, just where I might have taken his pulse had he been healthier. A fresh adhesive covered the cotton gauze and brownish anti-bacterial solution I’d placed over his lower right neck.

“Yeah,” I said as we walked out of the room to review another patient’s chart.

I wondered if the ICU staff would mind my changing the radio station, just in case the patient could hear but not tell us he preferred WQXR.

“There’s no way I would let this happen to me,” I remember thinking.

—–

This month, a report in the ACS journal Cancer indicates that most U.S. physicians don’t talk with their patients about end-of-life issues until death is imminent, if they do so at all.

The study, based on canvassing over 4000 doctors who care for cancer patients in California, North Carolina, Iowa and Alabama revealed that only a minority of physicians would raise the subject of a DNR (do not resuscitate) order or the possibility of hospice care for a patient with metastatic cancer with a life expectancy of 4-6 months. The article has generated considerable, appropriate attention in the press and for good reason – it bears on health care costs, patients’ rights, doctors’ communication and time constraints and a host of points relevant to the practice of medicine in 2010.

For purposes of this post, today, what I’ll say is this much:

Don’t wait for your doctor to talk to you about death and dying. Be proactive about your wishes and the kind of care you wish to receive, especially if you’re sick with a serious medical condition. Take the initiative – document your end-of-life preferences as best you can, according to the law of your state, and tell your physicians about any limits you’d like to set on the care you might receive.

It’s a conversation worth having, early.

——-

Here’s a very-partial list of resources for people who’d like to learn more about advance directives, living wills, DNR orders, hospice care and other end-of-life concerns:

MedlinePlus on Advanced Directives;

New York State: information on Health Care Proxy forms and DNR orders

Family Caregiver Alliance on End-of-Life Choices

Hastings Center on End of Life Issues

American Hospice Foundation

Cisely Saunders Foundation

Hospice Foundation of America

The National Hospice and Palliative Care Organization

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How Well Do You Really Want to Know the “Red Devil?”

I know what it’s like to get the “red devil” in the veins.

You can learn about Adriamycin, a name brand chemotherapy, on WebMD. Or, if you prefer, you can check on doxorubicin, the generic term, using MedlinePlus, a comprehensive and relatively reliable public venture put forth by the National Library of Medicine and National Institutes of Health. If you’re into organic chemistry, you might want to review the structure of 14-hydroxydaunomycin, an antibiotic and cancer therapy first described 40 years ago in the journal Biotechnology and Bioengineering.

from the National Center for Biotechnology Information (NCBI) database, http://pubchem.ncbi.nlm.nih.gov, accessed 12/11/09.

from the National Center for Biotechnology Information (NCBI) database, http://pubchem.ncbi.nlm.nih.gov, accessed 12/11/09.

When I was a medical student, I studied some facts about doxorubicin hydrochloride, enough at least to answer a few questions during pharmacology exams. Later, as a resident in internal medicine, I knew the drug to be an anthracycline, a chemotherapy that intercalates into DNA, wreaking havoc in cells’ genetic material and reducing the replication potential.

As an oncology fellow, I prescribed and administered the clear, intense red fluid to patients with lymphoma and breast cancer. I learned to be careful: if the medicine slips from the intravenous catheter and enters the nearby, tender tissue below the skin, it can harm. The drug commonly causes hair loss and stomatitis; mouth sores can be so painful it hurts to eat, even when the nausea doesn’t squelch your hunger, or talk. Adriamycin affects the bone marrow, where blood cells are produced, and heart.

It’s not an easy drug; my patients knew this and so did I.

This month marks seven years since my first dose of Adriamycin, part of the “A/C” regimen that’s sometimes given to breast cancer patients. Was it worth going bald, getting anemia, sluggishness, mouth sores, chemo brain and all else that I experienced? Yes; I have no doubts. But I was lucky; my tumor was small and I needed only a few cycles.

I never knew Adriamycin as the red devil until a few years ago when a friend’s stepmother, undergoing treatment, used the term in an email.  She’s a woman who read lots of blogs and shared her experiences with other breast cancer patients online. I realized that despite working in an academic medical center and regularly communicating with physician-friends and oncologists at meetings, I still had a few things to learn.

Now that I’m writing about cancer, I wonder what sorts of information people really want or need to make informed decisions. I suppose some would like to know the chemical structure of doxorubicin before receiving such a potentially poisonous, possibly life-saving drug. Maybe a patient’s husband, or daughter, would seek details about the half-life, metabolism in the liver, side effects and more.

When I received my chemotherapy, I didn’t want to read about breast cancer or treatments. Rather, I chose an oncologist I trusted and liked. Then, for the most part, I followed her advice. But this sort of strategy’s not for everyone, particularly for patients who don’t know their doctors as I knew mine. Besides, most cancer patients aren’t already board-certified oncologists.

With so much available data at our fingertips, some patients will amass many resources about their condition. Others will be more passive, mainly listening to their physicians or perhaps, to friends and family members who do the research on their behalf. To a large extent, it’s a matter of personality –

Ultimately, you can’t know everything about Adriamycin until you’ve had it in your veins. Whether being familiar with the chemical structure makes a difference, is less certain.

What’s clear is this: with so much information at our disposal, there’s an opportunity for patients to help doctors make better decisions.

(all links accessed 12/11/09)

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Getting the Math on Mammograms

The latest news’ focus on the breast cancer screening madness is about money.

So let’s do the math:

First, for argument’s sake, let’s say the U.S. Preventive Services Task Force is right – that to save the life of one woman between the ages of 40 and 49, on average, you’d have to screen some 1903 additional women every year or so for a period of 10 years.

This is, admittedly, a huge assumption; the panel analyzed two decades’ worth of data, some unpublished, involving complex models applied to millions of data points (humans) amassed in imperfectly-collected data sets that vary in size, scope and accuracy.

Next, let’s say the cost of a mammogram is $150, around what Medicare pays (yet another assumption, but we need to keep this simple or we’ll never get a sense of what’s really at stake here).

So if 2000 women (I’m rounding up) undergo annual screening for 10 years, the bill would come to $300 thousand per year, for a total cost of $3 million over a decade.  If those same middle-aged women were to get their mammograms biannually (every other year), the cost would be roughly $1.5 million per life saved.

This, the so-called cost of screening mammography for women between the ages of 40 and 49 (let’s call it “X”), is all over the news in various calculations, some that get closer to the right answer than others.

But what’s the cost of caring for one 45 year old woman with metastatic breast cancer?

Let’s call that amount “Y.”

Even the heartless among us would admit that we need to subtract, X-Y, to determine the financial cost of breast cancer screening to save one middle-aged woman’s life.

An insurance executive might say it’s in the range of $400 thousand, or a million dollars, or maybe even two million, if the woman lives long enough to go in and out of the hospital over the course of five years, undergo multiple surgical procedures, have semi-permanent intravenous catheters inserted and removed, suffer infections from those requiring at-home multi-week courses of intravenous antibiotics, all of this besides, of course, receiving chemotherapy, radiation, hormone treatments, incalculably expensive antibody infusions and newer, targeted therapies, followed by hospice (hopefully) or ICU care in the end.

Quick answer: maybe it’s cost-effective, or nearly so, to do screening mammograms on asymptomatic women in their forties.

But consider –  if the expert panel’s numbers are off just a bit, by as little as one or two more lives saved per 1904 women screened, the insurers could make a profit!

By my calculation, if one additional woman at a cost of, say, $1 million, is saved among the screening group, the provider might break even.  And if three women in the group are saved by the procedure, the decision gets easier…

Now, imagine the technology has advanced, ever so slightly, that another four or five women are saved among the screening lot.

How could anyone, even with a profit motive, elect not to screen those 2000 women?

The truest answer, of course, is that the value of any one person’s life is inconceivably huge.  And that doesn’t even enter into the equation.

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