Friday, August 11, 2006

Opportunity cost, opportunity lost

“Opportunity cost” is a concept from economics. Wikipedia describes it as follows: “Opportunity cost is a term used to mean the cost of something in terms of an opportunity forgone (and the benefits that could be received from that opportunity).” So, for example, if a city builds a hospital on vacant land that it owns, the opportunity cost is some other thing that might have been done with the land instead.

How does this apply to chronic lymphocytic leukemia? Have I finally gone off the deep end and decided to talk about building hospitals in my lymph nodes?

Not quite. Let’s take a look at one of our favorite CLL phrases: “watch and wai
t.” Wikipedia describes this under the medical term “watchful waiting”: “Watchful waiting, also referred to as observation, is an approach to a medical problem in which time is allowed to pass before further testing or therapy is pursued. Often watchful waiting is recommended in situations with a high likelihood of self-resolution or situations where the risks of a therapy potentially outweigh its benefits.”

Well, in CLL, we know that self-resolution is not the usual outcome. We get the short end of the watchful waiting stick: the risks of therapy potentially outweigh its benefits.

The trick is, when do you stop watchful waiting and start treating?

In some patients, this is an easy call -- the hemoglobin and platelets are crashing, there is fatigue that noticeably impacts quality of life, night sweats resemble the Great Flood, lymph nodes are popping up like well-fed prairie dogs, and so on.

In other patients, the call is a bit more difficult -- perhaps the hemoglobin and pla
telets are fine, but the lymphocyte doubling time is less than six months, or perhaps the lymphocyte count is normal but nodes are growing into little tennis balls. Looking at prognostic factors such as IgVH mutational status and FISH deletions may provide a little clarity, but sometimes not much.

The NCI Wor
king Group guidelines were written in 1996 to help doctors know which red flags to watch for. But there is no rote approach to starting treatment, and often no general consensus on when, exactly, to do it. Doctors have their individual opinions, and medicine is still an art. As we all know, artists range from the paint-by-numbers type to Rembrandt. Many of us have met the former type of hem/onc, and some of us have met the latter. Indeed, I could go on here, comparing some hem/oncs to impressionists like Monet, some to modernists like Picasso, some to surrealists like Dali, and some to elephants at the zoo painting with brushes in their trunks.

“Opportunity cost” in CLL

But let’s get back to “opportunity cost.” I will define it in CLL terms: Opportunity cost is what happens when you watch and wait too long. It’s what happens when symptoms get so far out of control that they are either 1) not successfully controllable, or 2) controllable only by extreme measures that, had the disease been treated earlier, would not have to have been taken. By extension, then, opportunity cost in CLL can be the opportunity foregone to treat with less toxic agents.

Patient advocates and some doctors have written about the dangers of premature treatment, which is indeed a problem in the CLL world, especially among hem/oncs for whom CLL is an afterthought or a dim memory in a textbook.

But the problem can, I believe, run in an opposite direction, and the opportunity cost can be an opportunity lost.

An extreme example, just for illustration, would be someone who uses EGCG, to no great avail, but who continues to do so right into marrow failure. Earlier treatment with something -- even Rituxan, or maybe low-dose chlorambucil combined with Rituxan and a low-dose steroid such as dexamethasone -- might have forestalled that day.

Say you’re a patient who would like to stick to the one soft-glove option we cu
rrently have readily available, at least in the USA: the monoclonal antibody Rituxan, perhaps with boosters such as GM-CSF. The problem you have is that even Rituxanites -- or would that be rituximabbers? -- such as myself freely admit that it isn’t all that effective in CLL as a single agent, and doctors heartily echo that sentiment. To the extent that it is effective, it appears to be more so at earlier stages and in patients with less disease burden. So, if you want to use Rituxan, which works best on smaller lymph nodes, is there an opportunity cost to waiting until one’s lymph nodes grow to 8 cm or 10 cm?

Rituxan might shrink a spleen that is 6 inches below the costal margin, but will it
work on a spleen that reaches halfway to China?

Most responsible physician artists, trained in the days when there was no soft-glove option available, tend to want to watch and wait until the horse is out of the barn, out of town, and in the next county. If the only available choice is hard chemo -- “where the risks of a therapy potentially outweigh its benefits” -- this makes sense.

But today we have the softer-glove array, however limited and imperfect (with the promise of possibly better agents, such as HuMax-CD20, on the way.) So, is there an opportunity cost to letting things go, to following the conservative approach that is the traditional way of watchful waiting?

If you want to play for time by using Rituxan, there may be. Now, some of these doctors might argue that some of us patients can make the mistake of using Rituxan too soon. Nobody said this was easy to finesse. And there is a paradox here: Patients seeking a conservative approach to treatment may treat sooner with Rituxan -- because of the way the drug works -- than traditional treatment conservatives would treat. We may find ourselves at odds with good doctors whose sentiments we appreciate.


Jenny Lou said...

I really enjoyed this piece because I truly believe that some people watch and wait too long and then are in a bad situation. If treatment is for quality of life, (until a cure is found), then I do not understand why some patient's will push themselves to a life of fatigue and feeling lousy. There are treatments that are not as toxic as FCR out there to make the quality of life much better while we wait. Enjoyed your topic.

Marc said...

Great post David. I even had to post a link to it on my blog.

Anonymous said...

Dr. Hamblin disagrees with you.

He has written in January 2006 (search his blog) that the patient should have his spleen removed, have transfusions, just about be on his deathbed before starting treatment.

Read his blog entry if you don't believe it.

Vance Esler said...

When patients feel good and feel healthy, it is difficult to convince them that they should take treatments that cause them to feel worse, even though just temporarily. I suspect many may be thinking, "I'll just wait and do something when I have to." This seems particularly so in older patients who have had family or friends treated in the older days when chemotherapy meant hugging a commode or spending half you life in the hospital.

From the doctor side, watching and waiting often makes sense because we don't want to start shooting, using up our ammunition, until we "see the whites of their eyes" -- that is, until we are convinced it will truly make a meaningful difference.

Watching and waiting makes the most sense in older patients because they may be just as likely to die from a heart attack or stroke as from the CLL. The frustration comes, however, when they don't die from something else, and then the CLL starts causing problems, and now you have to treat a patient who isn't in good shape anymore simply because they are older and more feeble. As David points out in this post, sometimes the window of opportunity closes before either the patient or the doctor realizes it.

Unfortunately, experience doesn't always help either, because the disease is so heterogenous. One person's CLL is not another's. What works for one does not work for everyone. And what works for many will not work for certain individuals. Sorting out who will do what requires a crystal ball, and I don't have one.

So there remain certain gambles. All anyone can do is make the best decision he can with the information available at the time, then don't look back and second-guess.

David Arenson said...

Thank you, Vance, for providing your reasoned perspective and for showing how this question of opportunity costs can be seen from the doctor's side of the desk.

I agree that there is little point in looking back and second-guessing. We make the best decisions we can at the time with the information we have and then we move forward from there.