Reducing Cancer Care Costs: Why Not Offer Neulasta in Smaller Vials?

This is the fifth in a series of posts on how we might reduce the costs of cancer care, based on 10 suggestions offered in a May, 2011 NEJM sounding board. We’re up to point 4:  oncologists should replace the routine use of white-cell-stimulating factors with a reduction in the chemotherapy dose in metastatic solid cancers.

In this section, the authors allude to what I think might be a cost-saving advance in oncology practice: why not make available lower doses of white blood cell (WBC) colony stimulating factors?

The issue is this: when people get high doses of chemotherapy, they’re compromised because the bone marrow doesn’t create new WBCs as it should. The risk of infection during chemo used to be so great that, in the 1980s and earlier, it was common for cancer patients to succumb to infection. With the advent of WBC stimulants in the early 1990s, the risks of infection during chemo dropped markedly.

These are complex and expensive drugs. And while I agree with the NEJM authors that chemotherapy is over-used, often, I don’t think it makes sense to cut down on potentially helpful doses or combinations of those drugs just because WBC stimulants are expensive.

Take Neulasta (pegfilgrastim), a long- acting stimulator of neutrophils manufactured by Amgen. This injectible drug costs over $ 2,000 for a single, 6 milligram vial. It’s supposed to be given every 2 weeks, although some oncologists might give it at a lesser frequency, depending on the chemo cycles. There’s only one size dose available for all patients; they’re all billed for the full 6 milligrams.

This is an ideal situation for Amgen, which takes in over $2000 for each 6 milligram vial. It’s far from perfect for patients who, even if there’s no toxicity, pay huge co-pays with each chemo cycle.

You can find some patients’ discussions of this issue at cancer support sites like these. There’s also a public correspondence between Medicare and the State of Wisconsin on the high costs of this drug.

Around 10 years ago, when I was practicing, I wondered why we couldn’t give some patients less than 6 milligrams of Neulasta. This would be useful in at least three situations: for patients who are physically small; for those who receive lower doses of chemo; and for people who are hyper-sensitive, for whom just a tiny bit is enough to raise the white count adequately. A frequent toxicity is bone pain; this is intense in some patients and, in theory, would be less problematic if a lower dose were available. Once, I almost got into administrative trouble for asking a pharmacist to draw up only half of the dose from a vial so that I might give a petite woman only 3 milligrams of this powerful drug.

Since then, nothing’s changed. I looked it up yesterday; there’s still only one dose of Neulasta: 6 milligrams.

So if Neulasta were sold in lower-dose vials, like 1, 2, 3 or 4 milligrams, patients could receive lesser doses, as is often appropriate. The costs of these drugs, when administered properly, might be halved, approximately, without compromising on recommended doses of chemotherapy.

Just my two cents, nothing more –

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Reducing Costs by Holding Back on Chemotherapy for Cancer Patients Who are Frail

This is the fourth in a series of posts on Bending the Cost Curve in Cancer Care, by Drs. Thomas J. Smith and Bruce E. Hillner, in a recent NEJM health policy piece. The authors’ third suggestion: to limit chemotherapy to patients with good performance status, with an exception for highly responsive disease, is surely one of the most controversial.

What they’re suggesting is a simple rule: “Patients must be well enough to walk unaided into the clinic to receive chemotherapy.” There are necessary exceptions, they point out, such as cancer patients disabled by another medical condition but who otherwise can carry out daily activities with relative normalcy. (I’ll offer an example: say a 50-year woman with multiple sclerosis who is wheel-chair bound but otherwise essentially well; she would be a candidate for treatment in this scenario.) But in general the authors would hold off on chemotherapy for cancer patients with a limited performance status  – a measure that oncologists use to assess how well, or disabled, a person is in their capacity to work, perform ordinary daily activities and care for him or herself.

I’m not sure I agree with the “walking” threshold, or ECOG performance status 3 or below, as the authors describe: “meaning that they are capable of only limited self-care and are confined to a bed or chair more than 50% of waking hours.” These criteria are subjective and problematic. But I do think the authors are onto a central, unavoidable issue in reducing health care costs. That is by limiting care, i.e. by rationing.

For elderly patients with cancer, especially for those who have significant other illnesses, it may not be appropriate for doctors to give chemotherapy and other, non-palliative cancer treatments. The authors don’t (dare) advise a particular age cut-off for therapy; they suggest using performance status criteria. They conclude this section of the paper on cutting cancer care costs with this statement:  “Implementation of such a simple threshold could dramatically decrease the use of chemotherapy at the end of life.”

The authors are right, that we (oncologists and other doctors) shouldn’t be in the business of routinely giving aggressive treatments to patients who are very old and frail, who are more likely to suffer harms of treatment than potential benefits. Not just because we can’t continue driving up U.S. health care costs indiscriminately, but because when very frail, elderly patients are given chemotherapy they’re less likely to recover after treatment. By not saying “no” to patients who are too fragile for a requested intervention, or by simply treating patients who are so feeble or demented, or both, that they’re unable to say “no” for themselves – such as sometimes happens in nursing homes and other chronic care facilities, doctors may cause more harm than good.

Some readers of this blog may be wondering how I can reconcile this position with what I’ve said about access to Avastin for women with advanced BC. In my opinion, patients’ age and, broadly, their functionality – if they can think and communicate seems at least as relevant as whether they can walk – should be factored into the risk/potential benefits analysis of almost any medical treatment.

So if we’re going to consider restricting cancer drugs and interventions based on cost, indirectly or overtly, we should account for patients’ ages, the potential length and quality of life to be gained: If there’s a 50 year old patient who might benefit from a costly cancer treatment, it’s likely that person will benefit more from that drug than would a 70 year old patient, or a 90 year old patient. It’s also more likely, but not a sure thing, that a younger, otherwise healthier patient will tolerate a given treatment with fewer side effects.

Hard to know where and how to draw the lines.

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Reducing Cancer Costs by Giving One Drug at a Time, Sequentially

This is the third in a series of posts on Bending the Cost Curve in Cancer Care, based on the late-May NEJM health policy piece.

Today we’ll consider the second of the authors’ suggestions: to limit second and third-line treatments to sequential monotherapies for most solid tumors. This particular suggestion, one of the few proposed with which I disagree, falls under the rubric of how oncologists’ behavior might be modified. The authors write:

A Cochrane meta-analysis showed that combination therapy had a small advantage over single agents for first-line therapy but caused more toxicity, and the review left unresolved the question of whether sequential single agents were a better choice.

…patients will live just as long but will avoid toxic effects. Second, society will benefit from cost reductions associated with less chemotherapy, fewer supportive drugs, and fewer toxicity-associated hospitalizations.

This approach is tempting, cost-wise, but may be simplistic: The purpose of combination chemotherapy is to give agents that work additively or synergistically, typically each at a lower dose, to achieve more effective treatment. In cancer, the best-studied multidrug regimens are in lymphoma, leukemia and breast cancer. Similar principles apply to antibiotic regimens for some infectious diseases, such as the drug “cocktails” for HIV or tuberculosis.

It could be that the authors are right for certain agents and some tumor types. But, likely, some drugs, including new targeted treatments given to patients who’ve already had several treatments, may be most effective and, paradoxically, less toxic – because the dose of each drug can be lower. The likelihood of resistant clones emerging may be diminished, too.

The problem we’re left with, of course, is that testing the different combination regimens will be costly. But I wouldn’t assume it’s better or necessarily cost-effective to give cancer drugs one at a time.

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Patients’ Words, Unfiltered, Medical Journalism and Evidence

Yesterday’s post was not really about Avastin, but about medical journalism and how patients’ voices are handled by the media.

L. Husten, writing on a Forbes blog, cried that the press fawned, inappropriately, over patients’ words at the FDA hearing last week, and that led him to wonder why and if journalists should pay attention to what people with illness have to say, even if their words go against the prevailing medical wisdom.

There’s a fair amount of controversy on this. For sake of better discussion in the future, I think it best to break it up into 3 distinct but inter-related issues:

1. About health care journalism and patients’ voices:

A general problem I perceive (and part of why I started blogging) is how traditional medical journalists use patients’ stories to make a point. What some of my journalism professors tried to teach  me, and most editors I’ve dealt with clearly want, is for the reporter to find a person with an illness, as a lead,  and then tell about the relevant news, and provide some expert commentary – with at least one person speaking on each “side” of the issue, of course – and then end the story with some bit about the patient and the future.

I argue that this form of medical journalism reduces the patient to an object, used by the story-teller in order to capture the reader’s attention. So, with exceptions and always with the person’s consent, I prefer to offer my own story, from my perspective, so as not to use the patient as a vehicle or literary device.

So it appears that Husten is OK with using patients’ voices to tell a story (and sell papers/clicks?), but not with presenting their views unfiltered if they don’t mesh with the party line or a particular point an editor wants to make. This lies at the center of the journalism issue.

(As an aside, a few recent published studies have found value in analyses of patient-reported symptoms, unfiltered even by their doctors.)

2.  About Avastin:

My impression is that some beast cancer advocates, including a National Breast Cancer Coalition representative who spoke at the FDA hearing, have chosen to “take the hit” on this particular issue because they need and want to appear rational. The straightforward-seeming argument is that the data show Avastin doesn’t work and is often harmful, so it shouldn’t be FDA-approved for women with metastatic BC. From the perspective of a BC advocacy group, it may not be worth pushing for a drug that helps only around 5% of patients.

The problem is there’s no biomarker for Avastin responsiveness, because this drug doesn’t target a particular genetic marker. Rather it works by cutting the blood supply, which could vary even within a particular patient’s mets in different organs. The only way to test if Avastin works in a patient is to give the drug, with informed consent, and see how it goes. Unlike, say, a bone marrow transplant, which runs in the range of hundreds of thousands of dollars and, once done, is irreversible, you can give one dose of Avastin and stop it, or two and stop it, if it doesn’t work or it is not well-tolerated.

Based on my experience as an oncologist and patient who’s received some risky interventions, I don’t think Avastin is more toxic than many or even most cancer drugs. Rather, its side effects have been heavily pushed by the media and public health/epidemiology academics in the past two years, who perhaps wish to make a larger point about this costly drug and evidence based medicine (EBM).

3. About evidence-based medicine: I’m in favor of EBM, especially in principle. The problem is that published medical data is too-often flawed and also, that some patients are, really, outliers.

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No Room For Emotion or Exceptions to the Rule (on Avastin)

My cousin testified before the FDA oncology advisory board on Tuesday about her experience taking Avastin. This is a tragedy, to deny the only drug that is keeping a 51 year old woman alive.

image from p.3 of today’s NYTimes business section

You have to wonder, are the advisory panel members so rational in all their behavior and choices? Are they always so razor-like in their oncology decisions?

Unlikely.

These experts have an agenda, here: It’s to be perceived as scientists, even when their knowledge is imperfect and exceptions to the rule stand right in front of their eyes. But clinical medicine calls for flexibility, and tailoring of treatment to each case, and caring about each person, including those who fall at the tail, or in this case better end, of any Kaplan-Meier survival curve.

What would Larry Kramer do about this, I’ve been thinking: He’d scream, really loud, so loud he might break his eardrums. He’d wonder why others, affected and near, aren’t doing the same. And he’d understand why this picture is on page 3 of the business section, and not on the front cover; it’s because people don’t want to look or see or know or think about it too much, because it hurts.

That is the normal heart, and this is a normal response to what’s happening to women with metastatic breast cancer.

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Cathy Wants a New Doctor and a Second Opinion

Last night the Big C returned, not surprisingly with an opening dream sequence. Laura Linney, portraying Cathy Jamison in the Showtime series, is running. The scene turns out to be a nightmare, and she awakens with a headache and her husband by her side.

Laura Linney portrays Cathy, hugging her son in Showtime's "The Big C"

OK so far.

Within a few minutes, Cathy’s young oncologist informs her that the interleukin 2 hasn’t worked; after two rounds of “chemo” the melanoma hasn’t budged. Sitting at his desk in the consultation room, he suggests she roll some joints for relief of headaches. She says she wants another opinion. It’s about time.

The main problem Cathy faces in this episode is that she can’t get an appointment with her oncologist of choice, Dr. Atticus Sherman despite calling, calling and calling. So finally she thinks out of the box: “That would be a coffin,” intimates her deceased, elderly neighbor Marlene who visits, spiritually, from Season 1.

So Cathy dons a suit and heels, and pulls a small suitcase with wheels – in the style of a drug sales rep – to work her way into the famed oncologist’s office. This desperate strategy, reminiscent of that suggested by journalist Elizabeth Cohen in the Empowered Patient book, and tried at least once by Samantha in Sex in the City when she had breast cancer, seven years ago or so on HBO, nearly backfires. But in a stroke of changed fate, the same doctor’s office calls Cathy to let her know she’s got an appointment for next week.

Such drama, just to get an appointment didn’t move me. But perhaps I’m too removed from this sort of painfully real situation for the countless, frustrated patients who can’t get appointments with appropriate specialists.

I was disappointed with the episode for other reasons. It wasn’t rich with ideas. There was no meaningful discussion of Cathy’s cancer, and only a shallow exploration of her feelings.

Like other TV comedies, this show was about everyday junk and family life: her son’s farting habit, her friend’s active sex life and pregnancy, her brother’s insanity, her dog’s seeming to be dead and then turning out to be alive. This (non) focus is fair enough, I suppose; when a person has cancer, they’re indeed surrounded by people in their family and friends who have their own needs and issues.

A particular beef is this: Clearly Cathy needed a second opinion; that’s been the case all along. But the script-writers made it too easy by having the young oncologist be utterly clueless and behaving inappropriately. The value of a second opinion would be clarified if Cathy had chosen to seek another doctor’s input even if she were receiving seemingly expert care from a solid, more experienced physician.

And where is the Internet in all of this? Her friend Rebecca (Cynthia Nixon) might be looking some stuff up. Or her brother, for that matter, who’s now said to be manic depressive, could be maxing out on free and potentially useful information. His anger at his sister would be more credible if it were less extreme and if he were less bizarre; his is not a fair or typical depiction of his stated mental illness.

How will Cathy’s appointment with Dr. Sherman go next week? We’ll see.

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What’s Next on the Big C? (Hopefully a Second Opinion)

(Hopefully a second opinion)

When I last wrote on The Big C, a Showtime series in which the actress Laura Linney portrays a woman in her forties with advanced melanoma, I considered some of the options she might choose when the series resumes next Monday night.

Laura Linney, in Showtime's 'Big C'

At the end of Season 1, she elected to try a course of IL-2 as was recommended by her young oncologist. Meanwhile, the FDA has approved Ipilimumab (Yervoy), an antibody treatment that revs up the immune system. And she’s in line, according to the script, for possible entry into a clinical trial that likely involves a targeted therapy, like vemu­rafenib for patients whose malignant cells have a genetic mutation in B-RAF.

What I expect Cathy will do, before anything else happens and she receives any additional non-urgent treatment for her advanced melanoma, is get a second opinion. She’s a smart, sensible sort; in retrospect it’s hard to believe she didn’t do this earlier on and before starting the IL-2 therapy.

I wonder, also, if one of her family members or friends will do some research about melanoma on the Internet. That would help her find a doctor with appropriate expertise, and better know what questions she should ask of the oncologist during the consultation.

That’s all on Cathy’s decision, until next week.

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Interleukin 2, Cathy’s Planned Treatment in the Big C

I’ve been toying with the idea of messing with a cable TV show’s plotline. At the first season’s end of The Big C, the story’s protagonist decides to accept a harsh and usually ineffective treatment for her advanced melanoma: interleukin-2 (IL-2).

Laura Linney as Cathy (Showtime image, The Big C)

Cathy, played by the actress Laura Linney, understands the goal is not for a cure, but to temporize her disease for six months, when she might be eligible for a new melanoma drug through a clinical trial. Her oncologist has already completed the paperwork, according to the old script. The season ends with Cathy in a hospital bed with an IV catheter, presumably receiving the IL-2, and dreaming.

So I thought I’d explain a bit on interleukins and IL-2 in particular:

Interleukins are proteins defined by their capacity to communicate between different populations of white blood cells (between leukocytes). The term was put forth by a group of scientists who studied lymphocyte activation in a 1979 paper in the Journal of Immunology. IL-1 was the first named interleukin, IL-2 was the second, and so forth.

IL-2 was first known as Lymphocyte Activating Factor (LAF). It went by other names, too, including Helper Peak, T-Cell Replacing Factor III, and B-Cell Activating Factor (BAF). It’s a powerful cytokine, a molecule that stimulates other cells to grow and mature. Most of it comes from T-cells. For decades, doctors have been aware of IL-2’s anti-tumor potential: it can stimulate the body’s natural killer, lymphokine-activated killer (LAK) and other cytotoxic cells to destroy malignant cells.

Now, human IL-2 is available in recombinant form. This means that researchers don’t need to purify the stuff from growing cells. Instead, companies use its genetic sequence to manufacture the protein in commercial labs, much in the way that other hormones are synthesized for medicinal use – like insulin or growth hormone. Recombinant human IL-2 is called Aldesleukin and sold as Proleukin.

When I was a resident and a fellow, I gave IL-2 to some cancer patients and monitored their reactions in clinical trials. It’s not an easy drug to take, as is emphasized in The Big C, set to resume on TV June 27.

This year, on March 25, the U.S. FDA approved an antibody treatment for advanced melanoma: Ipilimumab (considered here), now sold as Yervoy. Just yesterday, as considered in the Pharma Strategy blog (with a helpful chart of BRAF inhibitors), Roche/Genentech submitted an application to the FDA for approval of an experimental agent, vemurafenib (aka PLX4032), for treatment of patients with advanced melanoma.

What will Cathy do? I have no idea. But it’s good to know her treatment options are broadening.

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The Trouble With Ginger

A short post for Friday:

The Times published a short piece on ginger this Tuesday, on whether or not it relieves morning sickness. The conclusion is that it’s less effective for nausea in pregnancy than in seasickness and chemotherapy treatment.

When I was getting chemo, I received a gift of ginger tea. It didn’t help at all. Now, if I even sniff that stuff, I want to throw up.

Curiously, I have no problems with ginger in food. I use the fresh ingredient all the time.

No explanation –

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Thoughts on Geraldine Ferraro, and Myeloma

Like many New Yorkers, feminists?, hematologists and other people, I was saddened to learn yesterday of Geraldine Ferraro‘s death. The Depression-era born mother, attorney, criminal prosecutor, Congresswoman, 1984 Democratic VP-candidate and part-time neighbor to yours truly, succumbed to complications of multiple myeloma at the age of 75.

Abnormal plasma cells in a bone marrow sample said to be from a patient with myeloma (Wikimedia Commons). Plasma cells have nearly-round, eccentric nuclei and abundant cytoplasm (ES).

Myeloma is a cancer of plasma cells – specialized white blood cells (mature B lymphocytes) that make antibodies. Plasma cells normally develop in the bone marrow; they can exit into the bloodstream, which is why this condition is often called a tumor of the bone marrow or, occasionally, sometimes, as a leukemia. The term myeloma comes from Greek roots – muelo (which can refer to the bone marrow) and –oma, which in medical parlance has come to stand for a tumor and may derive from soma (body).

According to the NCI, over 20,000 North Americans receive a myeloma diagnosis, and approximately 10,000 die from the disorder each year. It tends to arise in older folks, and is slightly more prevalent in men than in women. According to the SEER data, in 2007 there were over 61,000 men and women in the U.S. alive with a history of this disease.

What’s notable to me, as a hematologist, about the former congresswoman is that she lived with myeloma for over 12 years: She survived with a disease for which there were few treatments available when she was on the Presidential ticket. This was partly due to luck – always a factor in cancer outcomes, as some cases are intrinsically more aggressive than others; partly due to her access to excellent doctors and good care; and, also, likely due to advances in myeloma treatment over the past two decades.

Some perspective: When I completed my fellowship in 1993, the median survival for someone with myeloma was less than 3 years. Starting around then, most specialists steered patients under the age of 65, and in some communities, older patients as well, toward autologous stem cell transplantation – an aggressive approach that’s been shown to prolong lives of patients in randomized studies. (For the record, I’ve never been convinced by those data.) More recently, old drugs like thalidomide and its fresher derivative, lenalidomide (Revlimid), along with new drugs like bortezomib (Velcade) have demonstrated efficacy in this disease.

In my opinion, what’s ahead for doctors caring for myeloma patients – and for the patients, even more so – in this next decade, is to see if these old and new pills might be better, less costly and less toxic than transplant-based treatment regimens.

A final thought on Ferraro’s care, is that it seems she benefited from the care of experts: hematologist-oncologists, transplant physicians and other specialists and subspecialists. With all the push now for more primary care doctors – who are indeed needed – her survival with what might have been a quickly terminal illness is a testament to the value of knowledgeable, well-trained physicians who keep up with developments in an evolving field.

As for the ceiling-breaking congresswoman, my thoughts are with her family now. She was a remarkable lady in many ways.

(all links accessed 3/27/11)

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Bristol-Meyers Says Ipilimumab Prolongs Survival in Metastatic Melanoma

This morning health business mavens are chirping with bright results for ipilimumab, a monoclonal antibody that can extend life in people with metastatic melanoma. If the new data – which I haven’t seen – are true, it’s good news for patients.

In 2010, melanoma affected 68,000 people in the U.S. and led to death in approximately 8,700. The WHO estimates that over 50,000 people die of this disease worldwide annually. For patients with metastatic disease, median survival is less than one year.

Last August, investigators reported in the NEJM that ipilimumab prolonged overall survival in patients with metastatic melanoma from approximately 6 to 10 months. Those findings were based on a randomized, multicenter Phase III study funded by Bristol-Myers Squibb, the drug’s manufacturer. In that trial, the most common serious toxicity of the drug was deemed to be immune-based diarrhea. Now, the drug is up for FDA approval and Bristol-Myers is saying that another study (“024” – presumably that’s short for CA184-024) reveals prolonged survival in patients with advanced melanoma. The findings will be presented at the ASCO meeting in early June.

Ipilimumab binds a molecule called CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) on the surface of T cells. It works as a double negative kind of immune activator: by blocking CTLA-4, which normally clamps down on lymphocyte activity, the drug fosters an anti-melanoma response by the body’s healthy immune cells. Like other monoclonal antibodies, Ipilimumab is given to patients by intravenous infusion. So it’s costly in itself, and because of the need for nurses to administer the drug, IV equipment, etc.

In principle, this drug might be applied to other tumors or infectious diseases to which the immune system doesn’t adequately respond. The NIH Clinical Trials website lists other protocols, including other tumor types, for which this drug is being tried.

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When Less Chemo is Just As Good, In Treatment for Acute Myeloid Leukemia (AML)

Today’s issue of the New England Journal of Medicine includes an article with the bland title Cytarabine Dose for Acute Myeloid Leukemia. AML is an often-curable form of leukemia characterized by rapidly-growing myeloid white blood cells. Cytarabine – what we’d call “Ara-C” on rounds  – has been a mainstay of AML treatment for decades.

The new report* covers a fairly large, multicenter, randomized trial of adult patients with AML. The researchers, based in the Netherlands, Switzerland, Belgium and Germany, evaluated 860 patients who received either intermediate or high doses of Ara-C in their initial, induction chemotherapy. According to the journal, “this investigator-sponsored study did not involve any pharmaceutical companies.”

The main finding was that at a median follow-up of 5 years there were no significant differences between the groups in terms of complete remission rates, relapses or overall survival. The high-dose Ara-C offered no clear advantage in any prognostic subgroup, including those with genetic changes that bear a poor risk. Not surprisingly, Grade 3 and 4 (severe) toxicities were more common in the patients who received higher doses of Ara-C. Those patients also had lengthier hospitalizations and prolonged reduction in their blood counts.

Why am I mentioning this report, besides that it hasn’t received any press coverage? First, because the findings might matter to people who have AML and are contemplating treatment options. But mainly it’s an example of how carefully dialing down some chemotherapy doses could reduce health care costs and lessen untoward effects of cancer therapy – in terms of early toxicities and, possibly down the line, fewer secondary malignancies – without compromising long-term outcomes.

*subscription required: N Engl J Med 364: 1027-36 (2011). The free abstract includes some details on the chemo doses.

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New Data for Avastin (Bevacizumab)

A new report was published on-line this afternoon by the Journal of Clinical Oncology (JCO). It covers a Phase III (randomized) clinical trial of Avastin (Bevacizumab) in women with metastatic BC. Over 1200 patients were included in the analysis, all with Her2 negative disease.

The design of the randomized study protocol was a bit unusual, in that the treating physicians could choose among a few, standard chemo options to give their patients – the so-called “backbone” for treatment for each cohort in the trial, along with hormonal treatment and the study drug: Avastin or a placebo. Avastin is a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF). It’s manufactured by Roche and is quite costly.

What the investigators report, now, is that women who received Avastin and any of the chemo regimens did better – in terms of what’s called progression free survival – than did those who received the same chemo and placebo treatment. The difference was a matter of a few months, on average, and there were no measurable change in overall survival. What this means is that in some women with metastatic breast cancer, Avastin appears to help keep the disease in check.

The study is called RIBBON-1, which I learned this evening would be for the first study of Regimens in Bevacizumab for Breast Oncology. Sounds lame, I know, but believe me – it’s hard for oncologists to keep trials straight without acronyms. Even with the acronyms.

It happens I know some women with triple negative BC who have benefited from Avastin. These women may be outliers on the curve, but they are real and they exist and I know them personally, in what should be the middle of their lives.

Maybe we, and the FDA, shouldn’t give up so fast on Avastin.

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More News On Lymph Nodes and Breast Cancer Surgery

Last week the New England Journal of Medicine (NEJM) printed a major research article on lymph node dissection in breast cancer surgery. When I first saw the Times’ recent headline, I thought it would cover this paper: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer.*

It turns out there were separate articles on axillary node dissection after sentinel node biopsy in breast cancer – one in JAMA and one in the NEJM – published a week apart. For some reason, the NEJM paper got little attention in the media.

In the work reported in the NEJM, investigators based at the Univ. of Vermont evaluated if the presence of occult metastases – cancer cells found upon further examination of dissected lymph node specimens after the sentinel nodes were deemed negative – affects survival in women with early-stage breast cancer. What they found was that yes, it does: there’s a small but significant reduction in overall survival and disease-free survival at 5 years in women who have “negative” sentinel nodes but turn out, upon more detailed path inspection, to have some malignant BC cells in the armpit.

Kinda scary for someone like me, who had a negative sentinel node. The Vermont investigators determined that 16% of us have occult mets. Of those, 11.1% would be isolated tumor-cell clusters (less than 0.2 millimeters in greatest dimension), 4.4% micrometastases (between 0.2 and 2 millimeters) and 0.4% macrometastases (larger than 2 millimeters), all as classified by the American Joint Committee on Cancer.

On the other hand, the results were generally favorable all-around:

“The 5-year Kaplan-Meier survival estimates for patients in whom occult metastases were detected were 94.6% for overall survival, 86.4% for disease-free survival, and 89.7% for distant-disease–free interval; the survival estimates for patients in whom occult metastases were not detected were 95.8%, 89.2%, and 92.5%, respectively.”

Some details on the well-done study I feel compelled to insert here, a vestige of my thrice-weekly-journal-clubs-in-academic-medicine days:

The Vermont study is strong from a statistical standpoint: The researchers examined stored pathology samples from 5611 women with operable, clinically node-negative BC who were already registered in a large multicenter clinical trial (NSABP B-32). The study participants were randomized to receive either sentinel node dissection or sentinel node dissection followed by full axillary lymph node dissection.

It was a prospective analysis, and the median time on study was just under 8 years. Of the 5611 women enrolled, 3887 (~70%) had negative sentinel nodes and sufficient pathology material available for evaluation. Oncologists treating the patients were “blinded” to the data regarding occult mets, so that they wouldn’t be influenced in their treatment decisions. Among the women with negative sentinel nodes, 1927 underwent sentinel node dissection followed by axillary node removal and 1960 got sentinel node dissection only (based on the earlier randomization).

One result not emphasized in the paper was that removing additional nodes, after the sentinel lymph node exam, didn’t affect the clinical outcome in women with or without occult mets. This finding ties in with this week’s JAMA report, covered separately.

It’s a long article, probably of more interest to pathologists and BC oncologists than to the average reader here. There’s a lot interesting detail, including subtle results of planned subgroup analyses, on the prognostic significance of different kinds (sizes) of occult mets.

I know from my experiences – mainly lately as a friend of people with BC who, in the past few years since sentinel node studies have become the norm – that these issues regarding the significance of occult mets bear on everyday decisions patients make together with their oncologists: how much chemo to take?; should I get radiation to the axilla if there’s a tiny cluster of cells found?; should we add Taxol to the regimen? etc.

These are very real, every-day questions in oncology, and the answers aren’t obvious. But I do think the carefully-established findings reported in this paper will shed light, in an incremental sort of way, on how to best treat BC in women who have negative sentinel nodes at surgery.

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Breast Cancer Study Shows No Benefit In Extensive Lymph Node Removal

Today’s Times leads with a story on surgical removal of lymph nodes in women with breast cancer. The dramatic digital headline, Lymph Node Study Shakes Pillar of Breast Cancer Care, made me tremble at first glance. The article by Denise Grady covers a new report* in the Journal of the American Medical Association (JAMA).

The key finding is that for women with apparently limited disease before surgery who undergo subsequent radiation and chemotherapy, taking out all the cancerous nodes from the axilla (armpit) has no advantage.

I read the original publication and took some notes:

The randomized study, carried out by the American College of Surgeons, involved 891 women with early-stage breast cancer without palpable lymph nodes in the armpit. All underwent lumpectomy and sentinel lymph node examination that was positive – meaning that pathologists observed malignant cells in a sentinel lymph node. Half of the women underwent complete axillary lymph node dissection, by removal of 10 or more lymph nodes, and half did not undergo removal of additional nodes. All of the patients received radiation therapy and the overwhelming majority (>96%) got chemotherapy. The proportions of women treated with endocrine therapy were similar between the two treatment groups.

What the researchers found was that removing additional glands didn’t improve survival in women who had positive (involved) sentinel nodes upon lumpectomy. Survival was measured at 5 years, and the median follow-up was 6.3 years. There was no difference in overall or disease-free survival. This finding supports that for breast cancer patients who will have radiation and chemotherapy, it’s OK for surgeons to leave malignant lymph nodes in place rather than remove those by more aggressive surgery.

Why this matters:

In the majority of BC patients, the lymph nodes in the armpit are not noticeably enlarged at the time of diagnosis. But one in five will have a malignant node detected at surgery. Up until now the standard of care would include a complete axillary lymph node dissection in those women. This procedure can lead to lymphedema, a condition of chronic arm and hand swelling that can be painful and disabling. Lymphedema affects a small but significant fraction of the growing ranks of women – approaching 3 million in the U.S. – who are alive after breast cancer treatment.

According to the Times article, the new research findings could eliminate the need for axillary lymph node dissection in as many as 40,000 women in the U.S. each year: “The discovery turns standard medical practice on its head.”

I’m not so sure I’d go so far as saying that – mainly because I don’t find the results surprising. But I do think it’s a study that matters: The implications bear on costs of breast cancer care (and, yes, on the “costs” of mammography and finding BC) and should have a positive effect on the quality of life for millions of women living after breast cancer treatment. There’s the potential to reduce surgery, and its complications, for the majority of new breast cancer cases.

Why aren’t the results surprising?

Breast cancer treatment, and our understanding of breast cancer biology, has advanced steadily in the past 25 years.

Now it’s routine to give treatments – like chemotherapy, hormone modulators or antibodies like Herceptin – that target breast cancer cells where-ever they reside in the body. The whole point of adjuvant therapy is to destroy malignant cells remaining after surgery. If there are some residual lymph nodes with malignant cells in the armpit region, those would likely be destroyed by chemotherapy and other treatments, combined with radiation to the affected chest and underarm area.

What are the study’s limitations?

What’s not adequately addressed is the situation for women who undergo mastectomy and don’t get radiation, as is standard after lumpectomy.

Another limitation is the study’s relatively short follow-up, of just over 5 years. This is a valid concern in any study of BC survival, but my own opinion is that the axillary node intervention is unlikely to result in a big difference later on. That’s because in 2011 what matters most for treatment decisions, after diagnosis and initial surgery, is the nature – in terms of genetic and molecular features – of the malignant cells.

It happens the NEJM ran a relevant paper on sentinel node dissection last week; we should explore those findings, tomorrow.

*subscription required

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An Oncologist Considers Rare Lymphomas in Women With Breast Implants

I have to admit that when I first read about the FDA’s report tying rare cases of anaplastic large cell lymphoma to breast implants, my mind raced with a strange blend of excitement, intense interest and concern. My thoughts shifted from “wow, that’s really interesting” to “exactly what did the FDA find” to “should I be worried?”

So I’ve decided to write this morning’s post from my perspective as an oncologist who spent roughly 15 years of her life studying the causes of lymphomas and related blood malignancies. Some readers of this blog, who fortunately at this point in ML’s slow-but-steady growth are mainly strangers, may be unaware that understanding rare lymphomas was what I lived for in my research work, which occupied the bulk of my time and thought, which I loved very much (as strange as that may seem to some) and which I miss intensely, still, today.

The reality, as very-carefully documented by the FDA in its excellent analysis (which, in my opinion, far surpasses that of most case series reported in the medical literature; I’d give the agency an A+ for detail, thoroughness, clarity and openness about the limitations of the findings thus far), is that these cases of ALCL are few and far between: a total of 60 cases, worldwide, as I reviewed in yesterday’s post. Sometimes just a few cases are indicative of a problem, and I think that is exactly what’s going on with these rare lymphomas.

The pathology is interesting: Essentially all of the ALCL cases are T-cell derived and express CD30. Anaplastic lymphoma kinase (ALK) was negative in each of 26 cases examined for that receptor. The findings are plausible in the context of an aberrant immune response – which can occasionally become malignant – to a foreign body or particular antigen associated with the implants. These oddly uniform characteristics among these rare lymphoma cases support that the FDA’s findings are not random.

Most of the ALCL tumors were limited to the area of the implant capsules, and could – as best I can tell from the few reports – be treated by removal of the implants and affected, adjacent breast tissue. These don’t appear to be aggressive lymphomas, as are some ALCL’s. I would go as far as to speculate that these might indeed be antigen-driven tumors; in this light, it would make sense in principle and in practice to treat these by removal of the implants, at least as a first-line approach.

So if I had a patient with this condition, I’d tell her that these lymphomas are very rare and, when they do arise, can usually be treated by removal of the implant. But I wouldn’t down-play the risk, which is tiny but real.

As an oncologist, I found most of the coverage of the FDA’s alert disappointing, the discussion dominated by plastic surgeons’ reassurances and device makers’ dismissals. Statements like “a woman is more likely to be struck by lightning than get this condition” – proffered by an Allergan spokeswoman as quoted and emphasized in the WSJ Health Blog, Bloomberg News, LA Times and elsewhere – are not helpful to women with implants who are genuinely concerned about their health.

Because I understand that once a woman has had one form of cancer, her risk of developing another tumor is elevated – from whatever genetic, environmental or other disposition she has for malignancy, and from treatment toxicity. Most of the women I’ve seen with implants after mastectomies have some problems considered minor – like thickening of the capsule and dimpling in peri-implant tissue. But these are the exact sort of abnormalities as described in the FDA’s alert, for which there is now a recommendation: evaluate and report cases to the FDA.

Ultimately this is an issue about informed consent – and I don’t mean by this the paperwork, but the reality of women with choosing, or not, to get breast implants. Doctors need more information about these rare lymphomas: how often these arise, why they occur, and how they should be managed so as to cause the least harm when and if treatment is necessary.

The FDA provides a helpful list of sources, from which I’ve selected those that seem most relevant (see reference page). Of historic interest, also, is a NEJM perspective from 15 years ago on the debate about rheumatologic illness, the public’s perception and risks associated with breast implants.

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FDA Reports on Association of Breast Implants and a Rare Form of Lymphoma

Yesterday the FDA issued an alert about a possible link between breast implants – saline or silicone – and a rare form of lymphoma called anaplastic large cell lymphoma (ALCL). These lymphoma cases are exceedingly rare, but the association appears to be significant.

The FDA identified a total of approximately 60 ALCL cases in association with implants, worldwide. Of these, 34 were identified by review of published medical literature from 1997 to May, 2010; the others were reported by implant manufacturers and other sources. The agency estimates the number of women worldwide with breast implants is between 5 and 10 million. These numbers translate to between 6 and 12 ALCL cases in the breast, per million women with breast implants, assessed over 13 years or so.

In women who don’t have implants, ALCL is an infrequent tumor, affecting approximately 1 in 500,000 women is the U.S. per year. This form of lymphoma – a malignancy of lymphocytes, a kind of white blood cell – can arise almost anywhere in the body. But ALCL cases arising in the breast are unusual. The FDA reports that roughly 3 in 100,000,000 women are diagnosed with ALCL in the breast per year in the U.S.

These are very small numbers. Still, the finding of ALCL tumors by the implant capsules is highly suggestive. Almost all of the implant-associated ALCL cases were T-cell type, whereas most breast lymphomas are of B-cell type. The lymphomas arose in women with both silicone and saline-type implants, and in women with implants placed for purposes or augmentation and for reconstruction after mastectomy.

The clinical features varied among the reported cases. From the FDA’s review:

… the median time from breast implant placement to ALCL diagnosis was 8 years, with a range from 1 year to 23 years. Most patients were diagnosed when they sought medical treatment for implant-related symptoms such as persistent seromas, capsular contractures, or peri-implant masses warranting breast implant revision operations. In each case, lymphoma cells were found in the effusion fluid (seroma) surrounding the implant, in the fibrous capsule, or within a peri-implant mass. Typically, there was no invasion beyond the fibrous capsule into the breast parenchyma.

Figure 1 illustrates the location of the reports of ALCL adjacent to the breast implant.

This illustration shows the breast implant placed under the skin and breast tissue. The implant is separated from the breast tissue by a fibrous scar capsule. ALCL lymphoma cells are shown in the effusion fluid between the breast implant and the capsule and attached to the capsule itself.

Figure 1. Presence of ALCL cells in close proximity to a breast implant. In most cases, the ALCL cells were found in the effusion fluid (seroma) surrounding the implant or contained within the fibrous capsule. ALCL is lymphoma, a type of cancer involving cells of the immune system. It is not cancer of the breast tissue, and typically, invasion of the lymphoma beyond the fibrous capsule into the breast parenchyma was not observed. Modified from Thompson et al, (2010).

With such a small number of cases worldwide, it’s hard to draw evidence-based conclusions regarding the appropriate treatment of these rare lymphomas. More from the FDA:

Treatment was reported for 20 patients. Most had the implants removed, and some went on to receive treatment with radiation and/or chemotherapy. Overall, the outcomes appeared to be more favorable than would typically be expected for systemic ALCL. Outcomes were reported for 19 cases. Of these, 14 patients had no evidence of disease at last follow-up. However, most cases were diagnosed with early stage disease, and follow-up on many cases was limited.

At this time, the FDA is advising health care providers to be aware of the possible diagnosis, to carefully evaluate breast implant patients with suspected ALCL, and to report all confirmed cases to the agency.

As for patients, the situation is troubling. The incidence of these tumors is quite low, almost immeasurable, and the prognosis – based on the few treatment reports – seems good. But many women do have some fluid, contractures, thickening and other complications around the implant capsules. Most of those physical aberrations surrounding the implants are not lymphoma.

It’s a Pandora’s box, but one that needs be opened. The problem is that if we biopsy every abnormality – such as a minor thickening or fluid accumulation adjacent to a breast implant – we’ll hike up the costs and, more importantly, the complications associated: With every needle stick there’s a risk of infection, additional scar formation and more. On the other hand, you wouldn’t want to overlook a treatable, early-stage lymphoma. Women need to know of the risks of implants, which can only be determined if doctors thoroughly investigate these sorts of complications.

The LA Times quotes Dr. Phil Haeck, president of the American Society of Plastic Surgeons: “I think there’s reason to be concerned about this, but there shouldn’t be reason for panic,” he said. According to that article: “Signs of ALCL associated with implants ‘are pretty dramatic. There’s a lot of swelling and pain. They won’t miss it,’ Haeck said.”

I’m not so sure. Lymphoma, including ALCL in my experience as an oncologist, can be very subtle.

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Why It’s a Good Idea to Get a Second Opinion, and Maybe a Third, But Rarely a Fourth

A few years ago I started writing a book on what it was like to be a cancer patient and an oncologist. This morning I came upon this section on second opinions:

Is it OK to get a second opinion?

Definitely. And there’s no need to be secretive about it, or to worry about hurting the doctor’s feelings. Second opinions are routine in fields like oncology, and are often covered by insurance. Be up-front: any decent oncologist can understand a cancer patient’s need to find a doctor who’s right for them, with whom they’re comfortable making important decisions. And in difficult cases, some specialists appreciate the chance to discuss the situation with another expert. So a second opinion can be beneficial to patients and physicians alike.

When things can get out of hand, though, is when patients start “doctor shopping.”  For example, I’ve cared for some patients with leukemia who’ve been to see over 10 oncologists. If you’re acutely sick, this sort of approach to illness can be counterproductive; it can delay needed therapy. From the physician’s perspective, it’s alienating; who wants to invest her time, intellectual effort and feelings for a patient who’s unlikely to follow up? Besides, oncology is the sort of field where each consulting doctor may have a distinct opinion. (If you see ten oncologists, you may get ten opinions…). Beyond a certain point, it may not help to get more input, but instead will cloud the issue.

As things stand, oncologists often discuss difficult cases with their colleagues. This happens at academic centers and hospitals, where tumor boards meet regularly to review the diagnosis and management of each cancer case, and informally in private practices, where physicians are likely to discuss certain aspects of treatment with their partners. For patients with very rare conditions, some oncologists will call experts in the field whom they may know through national meetings, journals, and other resources. What this means for patients is that through one consultant, they may be getting input of more than one expert, although they may not be aware.

So I recommend that patients with cancer, or any other serious or rare condition for that matter, get a second or third opinion about the best way to manage their illness. But at some point you’ve got to select one among those specialists, even if she’s not perfect, and stick with her at least for a while, until you have a good reason to switch or move on. Otherwise, you’re unlikely to have a doctor who cares when you’re really sick and, later, about your long-term well-being.

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Cautious Optimism for a New Melanoma Treatment

This morning’s news feed delivered some seemingly excellent news for some people with melanoma. At least until now, this form of skin cancer has been considered incurable when metastatic. In the last year, we heard details about the ups and downs of ongoing clinical trials of new drugs to treat the disease.

The Times reports that Roche’s experimental drug prolongs life in patients with metastatic melanoma whose tumors have B-Raf mutations. The new findings, based on a randomized phase III, open-label and industry-sponsored trial, BRIM 3, were first communicated in a press release yesterday. The company indicates that the study met its primary endpoints: Patients taking the experimental pill, RG7204, lived longer, and went longer without disease progression, than those patients in the control arm who received standard chemotherapy (dacarbazine) injections every three weeks.

The new drug – a pill usually given at a dose of 960 milligrams twice daily – goes by several names:

RG7204 (Genentech is a Roche subsidiary)

PLX4032 (Plexxikon has a partnership with Roche to commercialize and develop PLX4032)

RO5185426 (as listed at ClinicalTrials.gov and the NCI thesaurus)

Since the Phase III study opened in January 2010, investigators recruited patients at numerous medical centers worldwide. According to the Roche press release, nearly subjects were randomized to receive either the experimental pill (960 mg) twice daily or dacarbazine (1000 mg/m2) by intravenous every 3 weeks. Patients continued on their assigned drug until the disease progressed or they experienced unacceptable toxicity. The most frequent severe adverse events were skin-related, including another, less-aggressive form of skin cancer, and mild, reversible liver abnormalities. The most common reported side effects were rash, joint pain, hair loss and fatigue.

What I can’t find are published details, such as by how long life was prolonged in patients receiving the experimental drug. The NIH Clinical Trials site indicates the investigators aim to recruit 680 patients, and the Times indicates that since the trial opened, 338 patients were assigned to the chemotherapy arm of the trial, while another 338 received the Roche drug.

According to Amy Harmon’s report in the Times:

About half of the 68,000 Americans who develop melanoma every year have a mutation in a gene, called B-RAF, that goes awry, for reasons not well understood, signaling cells to grow uncontrollably. The Roche drug works by blocking a malfunctioning protein the gene produces in cancer cells, but leaving the functioning proteins in noncancerous cells alone.

Roche, in its press release, indicates that: “based on these interim analysis results, patients on the control arm of the study will have the option to crossover to receive RG7204.” The results will be presented formally at a medical meeting this year. (Presumably that would be the annual ASCO gathering in June.)

I’m eager to see the findings, the extent and duration of remissions, degrees of toxicity, and more. This could be another good example of targeted therapy – giving a treatment that’s designed to block a known molecular defect in a tumor – that might dramatically alter the prognosis, and way of life, for some patients with malignant melanoma. But I am cautious in my enthusiasm, as the reports so far, and data interpretation, come from the company that sponsored the clinical trial and would sell the drug if approved.

(all links accessed 1/20/11)

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addendum/clarification, Aug 2011: PLX-0432 was renamed vemurafenib.

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Does Cathy Make the Right Cancer Treatment Decision in the Big C?

scene from season finale, The Big C

“I don’t want to get sicker trying to get better and then just end up dying anyway” – Cathy, the 42 year old protagonist with advanced melanoma, on the Big C.

ML’s incoming search data suggest that some people out there are very determined to know exactly what happens to Cathy in Showtime’s new series about a young-seeming, middle-aged woman with advanced, presumably stage IV, melanoma. In last week’s review I elected not to give it away. Now I’ve reconsidered. So here’s a spoiler alert: Don’t read this post if you don’t want to know what happens to Cathy at the end of the Big C‘s first season.

After months of unusual and comfort zone-breaking behavior, Cathy reconsiders her initial decision to forgo treatment. She, possibly influenced and clearly supported by her husband’s enthusiasm for her middle-aged life and continued existence, indicates that she’s willing and ready to try treatment with Interleukin-2. Cathy seems to know something about the FDA-approved drug, which is generally toxic and ineffective in most melanoma cases. At one point, she lists its putative side effects, according to the show: “burning scabs all over my body, constantly throwing up, fluid on the lungs, my veins could shut down, I could die on the table…”

Nonetheless she decides to accept treatment:

“I’m gonna hang on as long as I can. And I’m going out ugly,” says Cathy, played by the actress, Laura Linney.

“It will never be hard for me to look at you,” responds her supportive husband Paul, portrayed by the actor Oliver Platt.

At this point Cathy’s hoping the Interleukin-2 (“interlaken,” as her husband keeps calling it, perhaps metaphorically, subconsciously, or else just simply) will keep her alive for six months, when she might or might not be eligible for an experimental anti-melanoma drug in a clinical trial.

So she goes for it: in the final scene she’s in the hospital, her mind cloudy, and dreaming. You may wonder what I think of her decision.

As an oncologist I’m half-relieved. The patient will, undoubtedly, die too soon – within months or a year or, if she’s lucky, maybe two years or even longer – because you never really know for sure about these things, if she doesn’t take any treatment. Deaths from metastatic cancer can be unpleasant and painful. On the other hand, conventional therapy for stage IV melanoma rarely leads to complete remissions and, essentially, never cures the disease.

I admired that the patient, until this last episode, maintained such a no-nonsense approach to her condition. Her perspective seemed more mature than her oncologist’s. Despite her weird and nearly unraveling behavior, she’s clearer in her priorities than many patients I’ve known; she seems to understand that a treatment might give her a few additional months but is very unlikely to help her get well and, likely, would make her sick for the duration of her life.

Sometimes oncologists get carried away with hope. What I liked best about the story is that she, the patient, was realistic in this. She didn’t want to take toxic medications in desperation, without reason.

As a patient, my feelings are mixed, too. I respected Cathy lack of passivity in her decision. Accepting treatment initially would have been the easier, “normal” thing in our culture. In effect, so far, Cathy’s taken control of what happens to her body. At the same time, I couldn’t help wonder – what if she tried it? Maybe there is a cure in the pipeline, and she’d be eligible for an experimental agent in a few months, and that drug would help her, and she’d live beyond middle age, or at least until she’s 45 or 46.

Today is Monday, but there’s no new Big C episode because the season’s over. We won’t know how Cathy fares with the Interleukin-2 for a while. Even though she is just a cable TV character, she’s in a position to teach us about oncology and living with cancer.

Hopefully the show’s producers will provide insights into immune treatments, targeted agents, clinical trials, informed consent and palliative care. (I will consider Interleukin 2 and melanoma in a separate post, to follow.) But given the TV scenario, do you think Cathy’s made a sound decision?

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