Monday, May 30, 2016

Cancer moonshot and slow-learners

Motivated by Vice President Biden's son's death at an early age from cancer, President Obama recently announced a new health initiative which he's calling the cancer 'moonshot'.  This is like a second Nixonian 'war' on cancer but using a seemingly more benign metaphor (though cancer is so awful that treating it as a 'war' seems apt in that sense). Last week the NYTimes printed an op-ed piece that pointed out one of the major issues and illusions belied by the rhetoric of the new attack on cancer, as with the old:  Curing one cancer may extend a person's life, but it also increases his or her chances of a second cancer, since risks of cancer rise with age.

Cancers 'compete' with each other for our lives
The op-ed's main point is that the more earlier onset cancers we cure, the more late onset, less tractable tumors we'll see.  In that sense, cancers 'compete' with each other for our lives.  The first occurrence would get us unless the medical establishment stops it, thus opening the door for some subsequent Rogue Cell to generate a new tumor at some later time in the person's life.  It is entirely right and appropriate in every way to point this out, but the issues are subtle (though not at all secret).

First, the risk of some cancers slows with age.  Under normal environmental conditions, cancers increase in frequency with age because they are generally due to the accumulation of multiple mutations of various sorts, so that the more cell-years of exposure the more mutations that will arise.  At some point, one of our billions of cells acquires a set of mutational changes that lead it to stop obeying the rules of restraint in form and cell-division that are appropriate for the normal function of its particular tissue. A tumor is a combination of exposure to mutagens and mutations that occur simply by DNA replication errors--totally chance events--when cells divide.  As the tumor grows it acquires further mutations that lead it to spread or resist chemotherapy etc.

This is important but the reasons are subtle.  The attack on cells by lifestyle-related mutagens like radiation or chemicals in the environment becomes reduced in intensity as people age and simplify their lives, slowing down a lot of exposures to these risk factors. However, cell division rates, the times when mutations arise, themselves slow down, so the rate of accumulation of new mutations, whether they be by chance or by exposures, slows.  This decrease in the increase of risk with age at least tempers the caution that curing cancers in adults will leave them alive for many years and hence at risk for at least some many more cancers (though surely it will make them vulnerable to some!)

Apollo 11, first rocket to land humans on the moon; Wikipedia

Competing causes: more to the story, but nothing at all new
There's an important issue not mentioned in the article, but that is much more important in an indirect way.  This is an issue the authors of the op-ed didn't think about or for some reason didn't mention or perhaps because they are specialists they just weren't aware of.  But it's not at all secret, and indeed is something we ourselves studied for many years, and we've blogged about here before: anything that reduces early onset diseases increases the number of late onset diseases.  So, curing cancer early on (which is what the op-ed was about) increases risk for every later-onset disease, not just cancer.  In the same way as we've noted before, reducing heart disease or auto accident rates or snake bite deaths will increase dementia, heart disease, diabetes, and cancer--all other later-onset diseases--simply because more people will live to be at risk.  This is the Catch-22 of biomedical intervention.

In this sense all the marketing rhetoric about 'precision' genomic medicine is playing a game with the public, and the game is for money--research money among other things.  There's no cure for mortality or the reality of aging.  Whether due to genetic variants or lifestyle, we are at increasing risk for the panoply of diseases as we age, simply because exposure durations increase.  And every victory of medicine at earlier ages is a defeat for late-age experience.  Even were we to suppose that massive CRISPRization could cure every disease as it arose, and people's functions didn't diminish with age, the world would be so massively overpopulated as to make ghastly science fiction movies seem like Bugs Bunny cartoons.

But the conundrum is that because of the obvious and understandable fact that nobody wants major early onset diseases, it seems wholly reasonable to attack them with all the research and therapeutic vigor at our disposal. The earlier and more severe, the greater the gain in satisfactory life-years that will be made.  But the huge investment that NIH and their universities clients make in genomics and you-name-it related to late-age diseases is almost sure to backfire in these ways.  Cancer is but one example.

People should be aware of these things.  The statistical aspects of competing causes have long been part of demographic and public health theory.  Even early in the computer era many leading demographers were working on the quantitative implications of competing causes of death and disease, and similar points were very clear at the time.  The relevance to cancer, as outlined above, was also obvious.  I know this first-hand, because I was involved in this myself early in my career.  It was an important part of theorizing, superficial as well as thoughtful, about the nature of aging and species-specific lifespan, and much else.  The hard realities of competing causes have been part of the actuarial field since, well, more or less since the actuarial field began.  It is a sober lesson that apparently nobody wants to hear.  So it should not be written about as if it were a surprise, or a new discovery or realization.  Instead, the question--and it is in every way a fair question--should be why we cannot digest this lesson.  Is it because of our normal human frailty wishful thinking about death and disease, or because it is not convenient for the biomedical industries to recognize this sober reality front and center?

It's hard to accept mortality and that life is finite.  Some people want to live as long as possible, no matter the state of their health, and will reach for any life-raft at any age when we're ill.  But a growing number are signing Do Not Resuscitate documents, and the hospice movement, to aid those with terminal conditions who want to die in peace rather than wired to a hospital bed, continues to grow.  None of us wants a society like that in Anthony Trollope's 1881 dystopic novel The Fixed Period, where at age 67 everyone is given a nice comfortable exit--at least that was the policy until it hit too close to home for those who legislated it.  But we don't want uncomforable, slow deaths, either.

The problem of competing causes is a serious but subtle one, but health policy should reflect the realities of life, and of death.  I wouldn't bet on it, however, because there is nothing to suggest that humans as a collective electorate are ready or able to face up to the facts, when golden promises are being made by legislators, bureaucrats, pharmas, and so on.  But, science and scientists should be devoted to truth, even when truth isn't convenient to their interests or for the public to hear.


David J. Littleboy said...

Hi again. I'm on your case because I respect you. But.

You wrote: "anything that reduces early onset diseases increases the number of late onset diseases."

I disagree with this idea. Strongly. First, you don't measure diseases by deaths, you measure them by deaths per unit population. Really. That's how we think about diseases.

Consider the following groups. (Different sizes since in real life they're different sizes.)

Group A: 10,000 people who died of early onset disease prior to 65.
Group B: 100,000 people who didn't acquire early onset disease prior to 65.
Group C: 10,000 people who didn't die of early onset disease prior to 65 because it was cured.

The RATE (yes, I'm shouting) of late onset disease in in each of groups B, group C, and group B + C is going to be identical.

You haven't "increased late-onset disease" by curing earlier onset disease, you've increased the SIZE of the group**. You have to divide by population size to understand what a disease is doing to you.

So the idea that curing early-onset disease increases the burden of late onset disease is wrong: it just increases the size of the population subject to the disease.

Second, everyone in group C is way happier to be in group C than in group A. It is a complete win for everyone in group C not to have died of bubonic plague. No one thinks that it's anything other than great news that we've cured bubonic plague (we have, haven't we?). No one in group C thinks they'd rather be in group A.

Third, if you want to argue that the folks under 65 are going to have to pay for treatment of late-onset diseases, ask how many of them are willing to volunteer to die of early onset disease*. That number is, of course, zero. To argue that curing early-onset diseases is anything other than a complete win for everyone involved is, sorry, completely dizzy.

*: And, FOURTH, it's worse than that. The major costs of treatment occur in the last months of life, and those costs are just as enormous, e.g., for early cancers as well as later ones (maybe more so, since people (both themselves and their families) are more bent out of shape at dying young). So normal taxation of earnings of folks who were saved from early-onset disease may make their deaths cheaper overall. Really. Four strikes is way beyond being out.

**: Quibble here. I probably need to look at not total population when counting deaths but "population over age X, where X is one standard dev. below average onset" or something like that. But, this is going to be a second-order effect, since in real life Group B is much larger than Group A. We have cured most early-onset fatal diseases, and aren't increasing the population much by saving people under 65. Which is why I changed the sizes of groups A, B, and C while writing this.

Fifth. Not all deaths are long and lingering. Other than Alzheimer's, most people are intellectually functional up to the end. And if you've been intellectually active, you're less like to get Alzheimer's. (Hey! There's a reason for my spending the time to argue with you.) (Oops, this doesn't really affect this argument; it's just supports my intuition that pretty much all human deaths are pure tragedy. Heck, I even cry for Justice Scalia; he seemed to be having so much fun throwing his racist, sexist, hate-the-poor/love-the-rich recalcitrant monkey wrench in the liberal project that I thought he'd live forever. It's sad to see someone having that much fun die.)

Well, actually it does have to do with this meme, since the feeling is that the dementias are a really vile way to go. But, really. Getting dementia at, say, 80 is better than dying of cancer at 55. By a lot.

Whatever. Keep up the good work thinking/arguing about these issues, and don't let the computer nerds in the peanut gallery get to you.

Ken Weiss said...

Thanks for these long comments. How and when one dies and how one thinks about that is very personal, of course, and of course I'm glad I've lived to my current age rather than dying of the plague decades ago! But if lots of people now die earlier of coronaries, they are not dying later of cancer or dementia-related disorders. If you are spared the early coronary you're at risk for a later disease that may be worse (or not, of course). The effort to prevent early onset disease is a good one, but many late-onset traits are not at all pleasant, and the reason for the hospice movement etc. is that so many are lingering in very poor states.

In a sense, if rates of cancer at age 80 are known, curing earlier heart disease doesn't increase the later 'rate', though the number will increase, a point I think was your main first one. Many early onset disorders are quick and less lingering so the number of expected person-years of misery may increase if earlier causes are eliminated. That's not an argument for letting us all go of plague at early ages, but our point was that there's no free lunch for a population, yet politicians seem eager to give the opposite impression. Preachers have always done something similar, except the immortal bliss they're selling isn't here on earth.

David J. Littleboy said...

" If you are spared the early coronary you're at risk for a later disease that may be worse (or not, of course)."

That later disease may look worse to observers, but ask the patient, and the patient always prefers the later disease. Really. You get decades of quality life by ducking that coronary. You always prefer a chance of getting at 80 than dying of a coronary at 55. Of course, you hope that medical researchers will be working on those in the meantime. (This is why smokers irritate me no end: the work spent on fixing smoke-induced cancers is work not spent on the diseases I'm likely to get.)

"Many early onset disorders are quick and less lingering"

That's certainly not true for cancer. Younger patients have better overall health and are better able to withstand aggressive treatment. Earlier detection means much longer times lived with the disease. (My reading is that if you subtract out the effects of less smoking, overall cancer death rates haven't been declining all that much. Of course, earlier detection means more early false positives and more people being treated for non-life-threatening cancers. Ouch.)

"the number of expected person-years of misery"

As you might guess, I don't buy this concept. At all. I'll take misery at 80 in exchange for those decades of guitar playing.

"but our point was that there's no free lunch for a population"

And I disagree. If your "population based science" is coughing up conclusions that are wrong for every individual, you are doing something wrong. Fixing a major cause of early death is a complete win for the patients concerned, and certainly doesn't make anything worse for the rest of the population. That sounds like a free lunch to me.

At the back of my head in all this is a lovely review article I read in Science one week. By some bloke who had just turned 100. His obituary appeared a few weeks later. My conclusion here is, of course, that he'd have had more useful things to contribute had he managed to make it to, say, 104.

Really. The bell does toll for thee. Every. Single. Time.

Ken Weiss said...

Well, there is no need to continue this discussion of things we partly agree on, but that avoid some of our main points. Hopefully, you'll have a long, happy life!