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MUSINGS OF A CANCER DOCTOR: Chronic

Sledge, George W. JR. MD

doi: 10.1097/01.COT.0000456305.23172.00
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Recently I was dining with friends, enjoying a pleasant Palo Alto evening on their porch. We noticed a family of quail walking on the ledge of the wooden fence that enclosed the yard, a mother and her brood of children. They hopped down into the yard. A peregrine falcon was sitting atop a tall tree, off in the distance. To me it was a thin smudge, featureless and motionless, perhaps a football field away. I suspect the falcon saw every minor blemish on my face. A falcon's vision is considerably better than that of an aging medical oncologist: they can see prey three kilometers away.

GEORGE W

GEORGE W

At some intellectual level I was aware that falcons were predators, capable of swift, violent action. My hostess even mentioned that she hoped the falcon had not seen the covey of quail. But we gave the falcon little thought until it fell from the sky, talons out, into the gathering of quail: a large, close blur, shocking in its suddenness, striking just feet from where we sat. I could have sworn I had seen it on that distant tree just seconds before, and that was in fact probably the case: falcons have been clocked at speeds as high as 242 miles per hour during their hunting stoop. They are, as I now know, the fastest animals on the planet.

One of the memes running through oncology right now is that of “cancer as a chronic disease.” If you enter it as a search term in Google you get approximately 324,000 hits. The idea taking hold is that we are entering a time when the average patient's cancer will be held in check through the judicious use of systemic targeted agents. Years will pass, the patient in generally good health.

I must admit that the phrase “chronic disease” always gives me pause when I hear it in relation to cancer. Historically, physicians separated acute illnesses such as pneumonia from chronic illnesses such as rheumatoid arthritis or diabetes. Prior to the advent of antibiotic therapies in the 1940s it was the acute illnesses that tended to kill; afterwards there was a progressive shift to chronic disease as a cause of death.

From a definitional standpoint, the standard definition of a “chronic disease” is “a long-lasting condition that can be controlled but not cured.” Most human solid tumors meet this definition, and are recognized as such by the CDC.

But I think that when we talk about “cancer as a chronic disease” we are usually thinking of something else: basically, the cancer goes into the stasis field of modern medicine and does not emerge to kill you. My patients certainly think in those terms.

There are, of course, some real candidates for what I might consider true chronic disease status, the oncoequivalent of “take your insulin and it won't kill you”: chronic myelogenous leukemia, controlled with imatinib, or an ER-positive breast cancer held in check with an aromatase inhibitor for prolonged periods. Or, to a somewhat lesser degree, metastatic HER2-positive breast cancer, or metastatic colorectal cancer, or renal carcinoma—all diseases where survival has significantly improved through the application of targeted therapies.

Scientifically this rapidly brings us to the question of treatment duration. Here we are trapped in empiricism. Mother Nature selected a year of HER2-targeted adjuvant therapy with trastuzumab as optimum. Not six months, not two years, but the time it takes the earth to circle the sun.

Or maybe not: adding a year of adjuvant neratinib to your year of trastuzumab may improve disease-free survival. Three years of adjuvant imatinib is better than one year for GIST tumors post-surgery. How about five?

For early-stage ER-positive breast cancer, 10 years of tamoxifen is better than five years is better than three years is better than one year: every time we have studied duration, longer is better. Though, of interest, the disease-free survival curves never quite plateau: are we are just delaying the inevitable?

And if so, is it really a chronic disease? If you stop treating rheumatoid arthritis and your joints get hot again, you may be miserable but you probably will not die, and you have a good chance of going back into remission with the same old drug: joints don't mutate. If you have metastatic breast cancer, you are walking around under the cloud of a death sentence, any temporary stay of execution provided by fulvestrant or T-DM1 notwithstanding.

Part of my problem with “cancer as a chronic disease” is exactly this: I know few individuals who would trade RA for metastatic cancer. Equating them seems somehow disingenuous.

I keep thinking of that peregrine falcon and the quail family. I have had a number of patients whom I have sheparded along for years, occasionally decades, with either estrogen receptor-targeted or HER2-targeted treatments. It is easy to contract and propagate the “cancer as a chronic disease” meme with such patients. The clinic visits become celebrations of the doctor's therapeutic virtuosity and the patient's family anniversaries, with drugs being switched in and out every now and then when the CAT scan demonstrates modest progression.

You can almost fool yourself into believing that the patient doesn't have a lethal disease. And then the falcon swoops in. “Chronic disease” can turn into “acute and lethal” in a shockingly brief period. One clinic visit you are discussing an upcoming high school graduation, and then the next you are having an end-of-life discussion.

I do not know why it is—perhaps because the patients have transitioned from being patients to old friends—but the death of a patient whom I have treated for a decade usually hits me harder than one who dies quickly. There is no intellectual reason for this: the death of a long-term survivor suggests I was actually doing my job, and I should be delighted that I have added many years of high-quality life rather than just a few. But it always leaves a bitter taste in my mouth. I doubt it is an experience a rheumatologist deals with very often.

Like some old soldier looking over the parapets at a distant enemy, I have learned to respect my foe's endless ingenuity, its treachery, its patient evil, and its almost maniacal drive to escape the barriers I try and throw up around it. We have, again and again, seen the ultimate failure of kinase-based approaches that have dominated the last decade, the consequence of a smart tumor's ability to mutate and evade.

The real “chronic disease” possibilities may lie within the realm of immune checkpoint inhibitors, where some (though certainly not all) melanomas appear to go into stasis for years and years, the body's immune system unleashed to keep the wolves at bay.

The idea of metastatic melanoma as a chronic disease still boggles the imagination, but it certainly looks to be a real possibility for many patients. Whether I want my T regulatory system ramped up for the next decade or two remains to be seen. I suspect we will be keeping the immunologists and rheumatologists very busy: more chronic disease.

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Naked Mole Rat

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Are there any other approaches that might turn human cancer into a true chronic disease? I present for your edification the naked mole rat. These are probably the ugliest mammals on the planet, almost disgustingly so. They are also the longest-lived rodents we have, clocking in at 30 years, a good life if living in total darkness underground in what one leading student of the species has described as a “dictatorship” is your cup of tea.

But here is the really interesting thing: they never die of cancer. I don't mean rarely, I mean never.

It doesn't matter how hard you try, either. Pump them full of carcinogens, and they just go on their merry, repulsive way, burrowing through the earth as if nothing had ever happened. And why is this? It turns out that the naked mole rat produces generous amounts of a high molecular weight form of hyaluronic acid, an evolutionary adaption that changes their skin to something quite stretchy and allows them to easily traverse underground passages. This form of hyaluronic acid has the pleasant side effect of walling off individual cancer cells before they can gain mass or metastasize.

The naked mole rat buries the cancer cell in concrete. This is a spectacular example of a microenvironmental approach to cancer.

Cancer cells live in neighborhoods, and for the past decade or so we have been enlisting the neighbors (blood vessels, T cells) in the neighborhood watch. These microenvironmental approaches have started to take off, and I suspect (based partly, but not entirely, on the naked mole rat story) that we are just at the beginning of such interventions. Hopefully we will not end up looking like naked mole rats.

Naked mole rats also have exceptional transcriptional fidelity. This error-free life also protects them from cancer. So taken are laboratory researchers with the naked mole rat that Science magazine declared it the “Vertebrate of the Year” in 2013, and there has been an explosion of scientific articles plumbing the rodent's exceptional longevity and freedom from cancer. And, of course, a naked mole rat genome project.

But back to the falcon and the quail. For a brief second after the falcon struck, we were unsure of the outcome. We couldn't see whether the falcon had succeeded in snatching one of the young covey. Then there was an explosion of quail, noisy, vectored in multiple contradictory directions, their panic reigning supreme. And then, much more quietly than the quail and more slowly than he had arrived, the falcon took off, talons empty: not today. Not today. Not today!

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