Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

Monday, March 26, 2012

On Sweating the Small Stuff

A few years ago there was a much-beloved (or beloved by Oprah, which is pretty much the same thing) self-help book called Don’t Sweat the Small Stuff…and it’s all small stuff.  Don’t Sweat was written by a pop psychologist named Richard Carlson, who preached the need to not let trivia consume your life. To demonstrate the point, he wrote 20 or so books, including Don’t Sweats for (a) men,( b) women, (c) teens, (d) with your family, (e) at work, (f) in love, and (g) about money.


His first Don’t Sweat book remained on the New York Times Best Seller list for 101 weeks, and his subsequent works were similarly popular forms of targeted therapy for neurotic men, women, teens, family members, workers, lovers, and financial strivers.


He probably would have not sweated a whole lot more, but he died at the age of 45 of a pulmonary embolus while on a book tour. Turgid blood flow is small stuff right up to the moment it kills you. As a frequent flyer myself, my first thought was “there but for the grace of God go I.” My second thought was: I need to do more deep knee bends on those long flights.


Like most people, I found “Don’t Sweat” a particularly useful tool for dealing with the concerns of others.  I neglected to fill out your W-2 form? “Don’t Sweat the Small Stuff.” I didn’t take out the trash? “Don’t Sweat the Small Stuff.”  George, your paper is late! “Don’t Sweat the Small Stuff.”


In contrast, the inability of others to fulfill my needs and desires can be pretty sweat-inducing. I want them to sweat the small stuff when it’s my small stuff, because my stuff isn’t small to me. What do you mean, you can’t have my car repaired until tomorrow? Why isn’t my hotel room ready? This is really slow fast food: what’s wrong with you people?


What Stuff is Small?

And that’s the problem, in a nutshell: what stuff is small?


It depends, not just on where you sit, but also on the timing of things.  The Chicxulub asteroid that wiped out the dinosaurs loomed large only minutes or hours before impact, obvious and inescapable. Sweating then was a bit too late. Change its trajectory by a trifling amount a year earlier and our ancestors would still be scurrying around hiding from velociraptors.


Small events -- one hesitates even to call them errors -- add up, like some malevolent compound interest. We’ve all seen the healthy patient who comes in for a test, suffers a minor complication, receives a drug to “manage” that complication, suffers a rare allergic reaction, develops end-organ failure, which results in a prolonged hospitalization, wherein the patient finally develops the hospital-acquired infection that leads to a fatal septic event.


The chain of events never happens quite the same way twice, but when you rewind the tape the initiating causal event is quite trivial, other than for its ultimate effect. The recent “checklist manifesto” movement recognizes the need to identify and sweat the small stuff, for that very reason. Most small stuff passes quickly, a minor inconvenience soon forgotten. But we never know when the small stuff will loom large, a dark onrushing shadow.


Oncologists sweat the small stuff because it isn’t small at all: we don’t want micrometastases to turn into extinction events. Changing the asteroid’s trajectory far away from the Yucatan peninsula is what we do for a living. One of the peculiarities of my job is that I almost never know when I have succeeded in changing the asteroid’s trajectory. I only know when I fail and Chicxulub crashes into my patient. This uncertainty has the benefit of encouraging, even enforcing, modesty.


Indeed, what is cancer but the accumulation, over time, of “small stuff?” The number of these small errors, we now know, is associated with prognosis.  The genomic folks have a measure, mutations per megabase, which correlates pretty well with a cancer’s lethality.


Our understanding of these errors continues to evolve, often in fascinating ways.  A recent genomic analysis published by Marco Gerlinger and colleagues in the New  England Journal of Medicine demonstrated the striking nature of intratumor heterogeneity. While the idea of intratumor heterogeneity is hardly new, this article well repays the reading in that it gives a measure of the magnitude of the problem.


Looking at multiple separate primary and metastatic samples from patients with renal cell carcinoma, two-thirds of all somatic mutations were not detectable across every tumor region, gene-expression signatures of good- and poor-prognosis varied within the same patient’s tumor sites, and tumor suppressor genes underwent distinct and separate inactivating mutations within the same patient’s cancer. Cancer is a big problem because of the sheer weight of all the “small stuff.”


Until we find some way of fixing DNA damage we’re stuck with trying (often unsuccessfully) to derail the oncoming train before it runs over the patient tied to the tracks of cancer’s double helix. Some times we create new errors, the massive induction of “small stuff” with DNA damaging agents and (more recently) PARP inhibitors. This is great when it works, but when it doesn’t, one wonders whether we are doing more harm than good, furthering malignant Darwinism.


Wouldn’t we rather fix, or at least prevent, those small errors? The scientific study of DNA damage repair has blossomed in recent years, and perhaps some day we’ll discover an efficient way of fixing broken DNA, little molecular tweezers snipping away the bad stuff, new patches sewn in, the fabric of your destiny rendered good as new by industrious onco-tailors. We can hope, but this is a ways off: we haven’t picked any DNA damage repair blossoms yet.


In the meantime preventing those small errors will rely on a successful understanding of epidemiology, its use in educating the public (avoid cigarettes, tanning salons, fried foods) and actively warding off mutagenic events (HPV and Hep B vaccines, SERMs).


‘Collision Avoidance Strategies’

By the way, there is a growing literature on how we might deflect killer asteroids. So-called “collision avoidance strategies” have attracted the attention of numerous astrophysicists intent on protecting MIT, Cal Tech, and Los Alamos from an extinction event. They pretty much all work on the principle of tackling the problem when it is far away: the astrophysics form of chemoprevention.


Your United States Congress, cognizant of the need for early asteroid detection, passed a law in 2005 requiring NASA to record 90% of the 20,000+ near Earth objects (NEOs) sized 140 meters or more in diameter by 2020. See them, take care of them, and avoid the fate of the dinosaurs. Being Congress, they authorized $5.5 million per year for this undertaking. And we complain about the NIH budget!


So here’s my motto: “sweat the small stuuf”. Oops. Delete. I mean: “swat the small stiff”. No, nit that: “Sweet the smell stuff.” Anyways, you know what I mean.