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Musings of a Cancer Doctor

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

Monday, December 10, 2018

By George W. Sledge, Jr., MD

 San Antonio is the largest breast-only cancer meeting every year, and arguably the most impactful. The meeting was started 4 decades ago by my mentor, Bill McGuire, and rapidly became the premiere venue for presenting both clinical and laboratory research. This year has been a good one both for breast cancer biology and treatment, with data that is immediately applicable to the clinic. I'll focus on just a few key take-home messages, involving treatment advances in HER2-positive, ER-positive, and triple-negative breast cancer, as well as the emerging science of genomics.

T-DM1: Best in Show

The highlight of the Symposium, from a clinical standpoint, was the presentation of the KATHERINE trial (please don't ask me what the acronym stands for). The trial started with a well-known observation: if you treat a patient with neoadjuvant therapy, and her surgery specimen demonstrates significant residual cancer burden for HER2-positive disease, she is at significant risk for early recurrence of breast cancer. This setting is one in which it is rational to apply novel therapeutic interventions in hopes of diminishing recurrence of disease. The high event rate with short follow-up times makes this an ideal study population.

KATHERINE, presented by Charles Guyer, MD, on behalf of an international group of investigators, randomized HER2-positive patients with significant residual cancer burden after neoadjuvant HER2-targeted therapy to either trastuzumab or to T-DM1 out to a year of total HER2-targeted therapy. The results, published simultaneously with the oral presentation in the New England Journal of Medicine, are striking (2018; doi:10.1056/NEJMoa1814017). T-DM1 improved invasive disease-free survival (the study's primary endpoint) by an impressive 11.3% at a median 41 months of follow-up; similar improvements were seen for distant disease-free survival, and overall survival—though early—is also trending in a positive way.

This represents a major win in HER2-positive breast cancer, and T-DM1 now joins the list of HER2-targeted therapies that improve outcome in the setting of micrometastatic disease. I suspect that this approach will receive rapid approval by the FDA and become the new standard of care in the post-neoadjuvant population. It will likely obliterate the use of post-neoadjuvant pertuzumab and/or neratinib, as pointed out by discussant Dr. Eric Winer, MD, and may well reduce the use of doxorubicin-based therapy as well.

All therapies have side effects. T-DM1 has both financial and therapeutic toxicity. In the study, T-DM1 patients had a significantly increased number of severe adverse events compared to the control trastuzumab arm, though the most important of these were reversible and relatively rare thrombocytopenia and transaminitis. But the benefits clearly outweigh the harms for the average patient considering such therapy.

The PHARE trial presented a long-term update on duration of therapy. PHARE tested duration of trastuzumab with a non-inferiority design, and the new 10-year results mirror the previous 6-year results in not rejecting the possibility of inferiority. A similar trial did reject, though the results are similar enough to PHARE and the major difference is the allowed confidence intervals for noninferiority. The T-DM1 results will likely render both trials irrelevant for high-risk populations, at least in resource-rich countries.

Stellar Results From SOLAR-1

PI3 kinase inhibitors have had a rough go of it. Though PI3K is a central node for several growth factor receptor pathways, and though PIK3CA is frequently mutated in both ER-positive and HER2-positive breast cancers, trials of PI3K inhibitors have largely been a bust, with minimal improvement in progression-free survival accompanied by significant toxicity, particularly in the form of hyperglycemia.

This meeting saw the presentation of the SOLAR-1 trial, a phase III randomized controlled trial of the selective PI3K alpha inhibitor alpelisib, comparing alpelisib plus fulvestrant to fulvestrant alone in metastatic ER-positive breast cancer. Though the trial recruited both PIK3CA-mutant and wild-type patients, the presentation focused on the patients with mutated tumors. In patients without prior CDK 4/6 inhibitor therapy, the addition of the study drug improved progression-free survival from 6.8 to 11 months. Overall survival trended positive but is immature for a truly confident analysis.

As with other members of this class of drugs, hyperglycemia represents a significant class effect, and a common management problem for patients and clinicians. I suspect real life, with older and less healthy patients, will offer up even greater hyperglycemia challenges for this agent. Nevertheless, this is the cheeriest trial presentation to date for a PI3K inhibitor, and the drug appears headed for the FDA.

An interesting side experiment in this trial involved the measurement of the mutation using ctDNA. Plasma ctDNA measures of PIK3CA mutations were highly concordant with tumor measures, and correlated well with PFS, suggesting that a simple blood test might allow us to "PIK" patients for this drug. Indeed, ctDNA was superior to tissue biopsy in predicting benefit.

In a related manner, this year's meeting saw a surge in ctDNA and circulating tumor cell presentations. None of these were definitive, though the gestalt from them was that this is a field that is rapidly heating up, both for surveillance for recurrence and progression, as well as prediction of therapeutic benefit for targeted therapy. The genomics field is rapidly progressing, and as prices fall and knowledge accumulates we are edging towards a day where liquid biopsies will guide treatment selection.

Immuno-Oncology for Triple-Negative Breast Cancer

Earlier this year, at the European Society of Medical Oncology meetings, we saw the first positive phase III trial of a checkpoint inhibitor in triple-negative breast cancer. The IMpassion 130 trial was updated (or cloned) for San Antonio, and though not much has changed, the results are worth describing. IMpassion 130 compared nab-paclitaxel alone to the same plus the PD-L1 inhibitor atezolizumab in first-line metastatic breast cancer. The trial enrolled patients with both PD-L1 positive and negative tumors.

Quite simply, there was no benefit seen for PD-L1 negative patients, and a statistically significant progression-free survival benefit for PD-L1 positive patients, from 5.0 months for the placebo arm to 7.5 months for the atezolizumab arm. Other biomarkers, such as CD8 and stromal TILs, added nothing to PD-L1 as a predictor of benefit. Though the presentation suggested an impressive overall survival benefit, with an increase from 15.5 to 25 months, these results are immature and were not supposed to be formally tested per the original hierarchical study design.

One concern arising from the initial data presentations is that the progression-free survival results do not, to date, look like what we would hope for: a true plateau in the PFS curves, such as seen in melanoma. This no doubt reflects the fact that, while we think of TNBC as the "heavily mutated" form of breast cancer, its mutational burden pales in comparison to melanoma, lung cancer, and MSI-high colorectal or endometrial cancer. Just not enough funny epitopes on the cell surface. Nevertheless, this is the first compelling evidence for therapeutic benefit of a checkpoint inhibitor in breast cancer. I cannot wait to see further follow-up.

Genomics

There were several wonderful presentations looking at the genomics of metastatic breast cancer. The genomic landscape of metastatic disease is now beginning to come into focus as data from hundreds of patients (many involving paired samples) become available. To summarize what this year's meeting suggested, comparison of primaries with metastases shows an increase (though not across the board) in tumor mutational burden and in specific mutations that represent potential therapeutic targets. The driver mutations identified represent a tractable number from a therapeutic standpoint, not dozens or hundreds, which is reassuring for drug developers. One presentation by Dr. Angus suggested that roughly a quarter of analyzed metastatic genomes had alterations for which FDA-approved drugs are available.

Within the past year, we saw the FDA approval of broad genomic panels, which also carry the Medicare imprimatur. As mentioned above, we are also beginning to see evidence that ctDNA is applicable to evolving breast cancers. These point to a number of fairly straightforward conclusions: first, that we will be able to measure tumor evolution in more-or-less real time, particularly that Darwinian selection induced by drug therapies; second, that we should be able to determine from such studies what treatments are best suited to keeping the patient's tumor in check.

Evolutionary biologists speak of the "Red Queen Hypothesis," derived from Lewis Carroll's Through the Looking Glass, in which Alice says "Now, here, you see, it takes all the running you can do, to keep in the same place." The Red Queen Hypothesis describes the evolutionary situation in which predator and prey co-evolve. Our "hunted" patients would like to stay several steps ahead of their vicious predator. Increasing knowledge of the genomics of metastasis, linked (for certainly it must be) to well-done therapeutic trials, should allow us to co-evolve, and perhaps get a bit ahead, of the pursuing beasts.

My Stanford colleague Christina Curtis, PhD, presented an updated analysis from the METABRIC consortium. METABRIC, published several years ago in Nature, used genomics to divide breast cancers into several integrative subtypes with prognostic significance, but never found its way into routine clinical use. At this year's meeting, Curtis and colleagues presented a detailed, clinically well-annotated update focused on several ER-positive integrative subtypes with increased risk of distant metastasis. These represent a substantial portion (roughly a quarter) of ER-positive patients and are associated with specific oncogenic drivers that could well serve as therapeutic targets, such as the fibroblast growth factor receptor and S6K1. Trials are in development to evaluate whether these findings will translate to clinical practice.

On a sadder note, we learned at San Antonio of the death of Charles Coltman, MD. Chuck led the clinical program where I trained in San Antonio, and had a distinguished career as a clinical trialist, primarily in the lymphoma field. A somewhat gruff, hard-charging ex-military man (we called him "COL. T Man, though never to his face), Chuck was a passionate advocate for clinical trials, serving for many years as head of the Southwest Oncology Group. He also co-chaired the San Antonio Breast Cancer Symposium for many years, first with Bill McGuire and then with Kent Osborne. I learned a lot about being an oncologist from him, and I mourn the passing of one of our field's giants.


Wednesday, December 5, 2018

A few months back, I attended a breast cancer meeting in Portugal. I started my last morning in Lisbon at 7:00 a.m. I knew from past experience that it always took more time to pack than I expected, particularly when I had been away from home for several days. There is something about being in a room I do not know, with socks and pants and shirts and keys and books randomly distributed on every previously empty table top, windowsill, and bathroom sink. I have left clothes and computer cords in many hotels over the years. So I spent a half hour packing the night before.

The flight to Newark was your usual United Airlines extravaganza. Halfway across the Atlantic the flight crew discovered that the ground crew in Lisbon had not serviced the toilets. Bad news, obviously, with no drink service for the last few hours and lots of nervous fidgeting by old folks. But the end result was that the plane got moved to the front of the line at Newark, so we landed 20 minutes early. No dark cloud without a silver lining.

I got off the plane, cleared customs, and headed for my flight to San Francisco. At Newark, the three terminals are connected by a light rail called Airtrain. I got on at Terminal B, headed for Terminal C. It wasn't a good time to ride Airtrain. It moved at a slow crawl. I could easily have outpaced it had there been a parallel walking path. And then, to make matters worse, the train went past the station stop, overshooting by about 30 feet. We sat there for a half hour, though in the mind it seemed far longer. When you want to get home after a long trip, time slows to a crawl as such inconveniences accumulate.

I got off the train, went through airport security, and walked to Gate 133 in Terminal C, arriving in the middle of boarding. After I sat, the pilot came on the intercom. There was some bad weather between New Jersey and California, but the crew had been working diligently on how to sneak around the thunderclouds, and he was certain we would arrive on time if not a bit early. A few minutes later, the doors were closed, and the plane readied for takeoff. It was at this point that one of the cabin crew noted, in the words of the pilot, and I kid thee not, that the plane had a defective life raft doohickey.

He assured us that it would only take 10 minutes to get this fixed. It was a trivial maintenance issue, not a major flaw. Now when an airline employee tells you that there will be only a 10-minute delay you know that they are being economical with the truth, to use Mark Twain's apt formulation. The next thing we heard was a flight attendant 's voice—I guess the pilot was too busy being embarrassed to share bad news—informing us that the flight was expected to land 40 minutes late.

Now, the above might be mistaken for another rant about the misery-inducing qualities of modern air travel: toilets that don't work because some employee couldn't be bothered to do his job, run-down airport facilities confirming the general perception of American civic decomposition, airline pilots bragging about how smart they are shortly before the flight gods punish that hubris with a "mechanical," and the courageous passing off of the delivery of bad news to a more junior employee. And, well, yes, those are all true. But that wasn't really my point.

My point was that all of these involved time, and my perception of time. When I travel, my overall sense of well-being largely revolves around when I unlock my front door, and that event is the summation of many small events. Because I fly a fair amount, I have missed flights, spent nights in awful airport hotels, hotels that I arrived at hours after my flight was supposed to have taken off, sat on tarmacs for hours all over the world, sat waiting for the gantry to roll down to the jet while local ground crews enjoyed late-night snacks, and stood for an hour in a long, winding taxi line. These all involved time, and my perception of it.

What is time? This turns out to be surprisingly difficult to define in any other than the most trivial of turns. The best physics is able to tell us is something like "time is what clocks measure." Yet time is the center of modern physics. Newton thought of time as a universal, what is now called Newtonian time. A standard 18th century meme was that of a clockwork universe, and God was the master clockmaker.

And then along came Einstein, who shattered Newtonian time. Time was a matter of your frame of reference. The faster you travel, the slower time moves. Einstein's time created the famous twin paradox, wherein one twin goes on a spaceship traveling close to the speed of light while the other stays here on Mother Earth. When the young space traveler returns, he finds a gray-hair sibling, even though only months have passed for the galactic traveler.

And while we haven't sent any astronauts away anywhere near the speed of light, time dilation is a real phenomenon, experimentally proven again and again, and practical for everyday life. The GPS and time clock measures my iPhone performs so effortlessly require adjustments for the time dilation caused by the satellites transmitting signals. They move fast enough around the earth, and so regularly, that if we did not make the adjustments our phone clocks would be off and Google Maps would tell me to turn left at the wrong street corner.

Most of the population is blissfully unaware of the physical reality of time dilation, or its effects on their lives. No doubt many would reject the very possibility of such effects as being either irreligious or a violation of plain old common sense, rather like some reject the Big Bang theory or the theory of evolution. But facts are stubborn things, and the universe is run by Einstein's playbook, not Newton's.

When I say "most of the population is blissfully unaware," I am not just talking about non-physics majors. There are populations of patients who experience their own personal time dilation, with altered perception of time, and while these alterations aren't associated with traveling near the speed of light, they are still eminently fascinating.

Take, for instance, the delightfully named but quite rare Alice in Wonderland Syndrome (AIWS). In AIWS, patients experience the sensation of visual distortions of body size (smaller), distance of external objects (farther away), auditory distortions (louder) and, finally, the sense that the passage of time is altered. To the AIWS patient, people may speak more quickly and things happen faster. Or, in some cases, that things move incredibly slowly. These alterations confer an altered sense of velocity (which, of course = distance/time) as well. AIWS has a very Einsteinian feel to it, if not an Einsteinian explanation.

AIWS patients have episodic attacks of time distortion. In one reported case in the neurologic literature, average reaction times increased during AIWS attacks, then returned to normal afterwards. There has been many a lecture or faculty meeting I've sat through where I wished I had the "time speeding up" version of the syndrome. Alas, I appear afflicted with "time slowing to a crawl" AIWS.

The "time slowing down" sensation is common in times of stress. I was driving home on an icy road a few years ago when my car spun out and headed for a tree. Time, or my perception of it, slowed. I saw the car approaching the tree at an agonizingly slow pace. I seemed to perceive every little branch and pine needle. Then the car hit the tree, my glasses flew off my face, and time sped up again.

It all happened in a few seconds, of course, but it seemed to go on a long time. That "time slowing down" experience was studied a few years ago by David Eagleman, now a Stanford neuroscientist, in a genuinely cool experiment conducted at an amusement park. Volunteers were raised 150 feet into the air and then dropped into a net, so-called SCAD jumping. It is a terrifying experience, apparently, and the perception that time slows down is a common one.

But does the SCAD jumper really see things in slow motion? In Eagleman's experiment, the jumpers wore perceptual chronometers, which flash numbers so briefly that one cannot perceive them under normal circumstances. If things really slowed down for the SCAD jumper, he should be able to read the numbers. Alas, this is not the case. The numbers are still a blur. Eagleman suggests that what has changed is not perception of time, but rather memory processing.

How do cancer patients perceive time? A 2011 Dutch study compared healthy cancer survivors with advanced cancer patients. Unsurprisingly, the healthy focus on the future, and the ill on the present. Somewhat to my surprise, patients with advanced disease experience the speed of time as being far slower than do healthy survivors. It is a frightening thought: being caught in a personal, inexorable horror where time slows to a crawl.

The neurologic basis of time perception has only been studied in recent years. Sofia Soares and her colleagues at the wonderfully named Champalimaud Centre for the Unknown in Lisbon, Portugal, have shown that manipulating midbrain dopamine neurons alters behavioral sensitivity to time. Transient activation or inhibition of dopamine neurons, in turn, slows down or speeds up time estimation. Does the cancer patient's experience of time have something to do with this phenomenon?

Ever since H.G. Wells, time travel has been a standard science fiction trope. The second law of thermodynamics seems a reasonable bar to traveling backwards in time: entropy is a beast. And even if you could, the paradoxes might get you: prevent your grandmother and grandfather from meeting, and you don't exist; if you don't exist, you can't prevent them from meeting, so you exist after all.

But I still can dream. Maybe I'd stay a day longer in Lisbon, have some fun in that lovely city, and avoid an awful flight. But then I'd be subject to the Airline Paradox: avoid one miserable air travel experience, and the universe artfully conspires to create an equally awful one. It seems an unalterable universal law, first discovered (perhaps) by Einstein while awaiting a flight from Berlin to Paris. Spooky action at a distance, or something similar.

Wednesday, December 5, 2018

We do not really see ourselves when we look in the mirror, and that is just as well. I only peer into the mirror during that brief period when I shave in the early morning, and then I just focus on not cutting myself. I'm barely awake, and shaving is a rote process devoid of even minimal thought. But a few days ago, I looked at myself, really looked at myself, looked more or less objectively at what I have become: the aging sun-damaged skin, the somewhat jowly cheeks, the sleepy-looking eyes. And I saw my hair.

Of course, I look at it when I comb: a center part, an attempt to provide some minimal order to what otherwise resembles a particularly untidy bird's nest. My hair used to be brown, then transitioned to salt and pepper, and now is mostly salt. Every time I go to the barber I see less black in the cuttings. And the hair itself seems coarser, more fragile, than I remember it. Someday soon I won't even be able to pretend: I'm just getting old.

Hair was the original biomarker of aging. Why does hair turn from a vibrant dark brown (well, that's my claim, any old photos notwithstanding) to a pale, pitiful shadow of its youth? Why did my hair follicles stop producing melanin? And why are my eyebrows still so discordantly dark? What's with that?

The shortening of hair follicle telomeres, those caps on the tips of our chromosomes, have been implicated in hair aging. A decade ago it was shown that if you re-introduced telomerase into epidermal stem cells you could reverse the effects of aging on hair follicles. In mice, anyways: it doesn't seem to have caught on in humans. Though I note, for the record, that one can buy Delfogo Rx Telomere DNA Cell Cream with Telomerase (Medical Grade) Anti-Aging SkinPro Repetitive Nucleotide Sequences from a company called SkinPro for just $45.59. And that's just one of many telomere-related products available on the Internet. Whether they are any better than hair dye is a question for others to answer.

My patients, of course, have a different take on the hair question. Hair matrix keratinocytes in hair follicles divide continuously, rendering them sensitive to many anticancer therapies, particularly chemotherapy. Every chemotherapy conversation eventually involves a discussion on the loss of hair, its timing, the relative merits of cold caps as prevention, the velocity of return, and the temporary waviness ("chemo curls") of the returning hair. Prescriptions for a "scalp prosthesis" are common; insurers, for some reason, won't pay for a wig. A colleague once wrote a scrip for a "total head prosthesis," which didn't fly either. Go figure.

Hair stories, for some reason, stick with me. I remember patients—usually those with metastatic breast cancer—who have chosen one chemotherapy over another based on relative amounts of hair loss. The conversation frequently starts with, "I know it sounds vain, but...," followed by my reassurance that there is nothing the least bit vain about a cancer patient wishing to look normal. For better or worse, hair is one of those things others judge us by and is the first thing one notices in meeting someone. None of us wants to be an object of undue interest, even pity, because we fail to wield a shock of embalmed scalp keratin.

I remember the patient who told me of her trip to the Department of Motor Vehicles when chemotherapy overlapped with driver's license renewal. A wig covered her scalp. As she sat there, the thought crossed her mind that the only people ever to check her driver's license were untrusting merchants cashing her checks and cops ticketing her for speeding. At the last second, she snatched the wig off, and the license showed her with a triumphant grin.

Then there was the woman who, on her last day of adjuvant chemotherapy, came to clinic wearing a fluorescent green clown's wig. Everyone she met that day heard the same thing: "Dr. Sledge did this to me."

And there was the young woman with long, beautiful blond hair who asked, "Dr. Sledge, when my hair grows back, will it be the same color?" Like an idiot I assured her that it would, which allowed her to say "Good. I won't need to use the Clairol anymore."

These are funny stories, but funny with a tinge of sadness, courage, even anger.

One last story, and this one haunts: the patient who, heading for hospice, said "I hope I live long enough to die with a full head of hair." In the grand scheme of things, hair may not have the same importance as hemoglobin, but it matters. We care. Ever since the Biblical story of Samson and Delilah, the loss of hair has been associated with infirmity, and re-growth with the return of strength.

And that's just chemotherapy. What intrigues me about hair biology is the extent to which it overlaps with cancer biology. The body loves to re-use biologic motifs, which is why the old idea that "targeted therapy" would be less toxic than chemotherapy turned out to be so wrong. If I administer an agent with EGFR-inhibiting qualities, my patients will develop a rash. Indeed, the rash was considered a crude biomarker for EGFR inhibitory activity. The rash is at least in part a function of the drug's effects on hair follicles, which are loaded with, and depend on, EGFR.

Or consider the JAK-STAT pathway. Oncologists care about JAK-STAT because pharmacologic inhibition of the pathway is a useful treatment for myelofibrosis. But inhibit the JAK-STAT pathway and patients with alopecia areata (which we now know to be an autoimmune disorder) rapidly regrow their lost hair. In contrast to EGFR inhibition, this is a positive side effect and has been embraced by the dermatologists. Topical JAK inhibitors are on their way to the clinic.

As a society we care a great deal about hair. I measure how much Americans care about something in terms of NCI multiples. The 2018 NCI budget is around $5.5 billion, whereas the amount spent on hair products is estimated at around $75 billion, or 13.6 NCI multiples. Think about 75 billion dollars-worth of gels, waxes, mousse, pomade, hair sprays, and volumizers. Add in hair coloring products. Also add to the pile all the hairstyling equipment: rollers, straightening irons, hairbrushes, blow dryers, and combs. Much of this equipment, Wikipedia informs me, already existed in ancient Egypt, though someone living on the edge of the Sahara probably didn't need a blow dryer.

Hairdressing is a rapidly growing occupation, with a current estimate of around 757,000 hairstylists in the U.S., not too far below physicians in total number. Hair stylists have been around a long time, as have doctors, and parallels abound between the two professions. Like physicians, they receive specialized training in special schools, and like them they are licensed by the state. And, like doctors, they can commit malpractice and can get liability insurance. There are lawyers who specialize in salon injuries. Reading one law firm's website, the injuries include cuts and abrasions, chemical burns, hair loss, allergic reactions, and slip and fall injuries (all that hair on the floor, I guess). It's like visiting an unexpected parallel universe.

Hair has its own history. Two Napoleon stories bear this out. A couple of decades ago, the case was made that the Emperor, having lost the battle of Waterloo and been exiled to St. Helena, had been poisoned with arsenic by his perfidious British captors. His end-of-life symptoms, the claim was made, were due to the poison, not the stomach cancer many had thought.

The claim seemed to have been backed up by forensic analysis of his hair, a lock of which had been kept by an admirer after his death. Screamingly high levels of arsenic were detected. When I started this blog, that was my memory of things. But it turned out to not be the whole story. Other investigators, skeptical of the claim, looked at locks of his hair collected at multiple timepoints (what is with early 19th century Frenchmen and their keepsakes?). It turns out that just about every hair sample was full of arsenic. What now seems likely was that the hair products of the time were loaded with arsenic.

So if arsenic did not kill the emperor, what about common, everyday ordinary hair products? There is an impressive literature on this subject. Hairdressers, who apply the stuff daily to women's scalps, suffer from slightly increased rates of multiple cancers. The data on the women receiving the hair dyes have disagreed. One recent article, for instance, said that hair dyes have no effect on overall cancer rates, but that African-American women using black hair dyes suffer higher rates. As with much of the epidemiologic literature, the hair dye literature is a morass, a deep bog of conflicting stories. Or so it appears to a non-epidemiologist.

Back to Napoleon. In 1812, the emperor invaded Russia with a huge army, which then suffered catastrophic reverses in a miserably cold winter retreat. Observers on the march home noted that bald men were the first to fall. While I don't know that it is a general law of thermoregulation, "don't invade Russia in the winter if you are bald" seems a useful dictum to live by.

So, my hair is gray. At least I have some. For now. Though I have no plans to invade Russia.

Friday, September 21, 2018

My wife and I were walking down the street recently when we came upon an old black Ford, lovingly kept up by its owner. I recognized it immediately as an early 1950s model of the sort my parents owned when I was a child. The Antique Automobile Club of America defines "antique" as a car over 25 years of age, so I guess this was an antique, but for a moment I was transported back to when it was new. And I was new, and not the antique I am now.

My first conscious memory was of waking up in the back seat of our black family Ford. I remember the car as having a high ceiling, though that memory may only reflect my own short stature. Cars in those days had no seatbelts, and there were no car seats for children, so I must have been sleeping on the back seat. I remember waking up with my mother and father talking to each other up front, and I remember the car stopping and getting out, and I remember literally nothing else happening before that experience. Even at the time, I remembered remembering nothing before that moment.

When was your first conscious memory? I must have been about 3 years old. Studies of first memory give ranges between 1 and 4 years old, with a plurality occurring at age 3, so I was distinctly average. The folks who study consciousness for a living say that "first conscious memory" is not the same thing as "first evidence of consciousness." That boundary has been pushed back to 2 months of age through the use of functional MRI studies. Still, I like to think that waking up in the back seat of a black Ford sedan as the moment that my consciousness, my own sense of myself as an independent individual, blinked on.

There are numerous—too numerous—definitions of consciousness, though I like the one used by Wikipedia: "the state or quality of awareness, or, of being aware of an external object or something within oneself." Consciousness is an exceptionally contentious subject, argued over endlessly by philosophers, biologists, neurologists, physicists (quantum theory—don't even ask), and just about everyone else at some time or other.

The philosophers have been thinking about this the longest and have the most interesting arguments. Descartes based his theory of philosophy on what he viewed as the solid rock of consciousness: cogito ergo sum, I think therefore I am. At the other end of the spectrum, a modern philosopher, the ever-entertaining Daniel Dennett, belittles what he calls the "Cartesian theater" of consciousness, viewing it as little more than an epiphenomenon, a largely irrelevant by-product of complex neural wiring in higher organisms.

As has happened so often in science, philosophy has given way to measurement. Whereas 20 years ago the science of consciousness was essentially nonexistent, at least in the sense understood by working scientists, today it is a robust field of discovery, propelled by novel technologies such as functional MRI scans, electro- and magnetoencephalography, combined with imaginative experimental designs. Several theories of consciousness have emerged from this work, the premier among which—as far as I can tell—is something called the global neuronal workspace theory.

The global neuronal workspace theory emerges from studies of visual inputs. Flash an image for a brief period—50 microseconds or less—and the visual cortex will light up on an fMRI, but nothing else happens. Longer exposures to the image light up not just the visual cortex but multiple areas of the brain. The image is now being shared across the global neuronal workspace, and multiple areas of the brain now have access to the input. This, in simple (overly simple—I'm not a neuroscientist) is the basis of consciousness. Anyone wishing a deeper understanding of consciousness should read Stanislas Dehaene's wonderful book on the subject. A competing theory, the integrated information theory, is also championed by many neuroscientists.

The parts of the brain involved in consciousness are quite specific, and particularly involve the cerebral cortex in the posterior portions of the brain: the parietal, occipital, and temporal lobes. You can lose your entire cerebellum and not have it affect consciousness.

Early philosophers and biologists separated humans from "lower" animals based upon their ability to form conscious thought. Current neuroscience isn't so sure, extending consciousness to many vertebrate species. Anesthetize a chimpanzee, paint a red spot on part of its anatomy it usually doesn't see, and when the animal wakes up in a room with a mirror, it will touch the spot, even moving the mirror to get a better view. This mirror self-recognition test is not a perfect marker of self-awareness, but the animals that pass it tend to be clustered at the upper end of the animal kingdom, neural capacity-wise: bottlenose dolphins and killer whales, bonobos, orangutans, Asian elephants, and Eurasian magpies; perhaps dogs. Human children typically pass the test at around 18 months of age.

And then there is the octopus. The octopus doesn't pass the mirror self-recognition test, though they do freak out when they see themselves in a mirror. But the octopus seems really smart to me. Peter Godfrey-Smith in his wonderful book, Other Minds, calls the octopus "the closest thing we'll ever see to an alien intelligence." The octopus has the brain capacity of a small dog, with around 500 million neurons (we have a bunch more). Weirdly, three-fifths of the neurons in an octopus are found, not in the brain, but in the arms.

Octopuses do not live very long: an elderly octopus is 3 or 4 years old at most. But in their prime they seem self-aware, and quite aware of their environment. They can identify, remember, and target individual humans in an aquarium environment. They are escape artists. They participate in play behavior. They are tool-users. They communicate with each other, in part, through chromatophores located in their skin. Think of having a conversation conducted in changing patterns and colors of skin pigment. And they are invertebrates, a half-billion years separate from our common evolutionary ancestor. They've evolved consciousness independently of us and our higher vertebrate relatives. They are deeply weird, and ineffably cool.

But back to us. We lose consciousness every day. We call it sleep, that pre-programmed disappearance—aside from those vivid dreams that sometimes intrude on the next morning's memory—of that conscious state that normally defines us. We think nothing of it, yet it is really quite wonderful and mysterious. One minute I am snoring, the next my alarm clock or a pager goes off and within seconds (OK, maybe a minute) I am conscious. We also induce loss of consciousness with regularity. Indeed, it's pretty much the definition of what it means to be a general anesthetic. Nothing wrong with that. The brain is good at re-initializing its consciousness programming.

It is the disappearance or alteration of consciousness during daytime and with disease that bothers us. Drugs and disease both disrupt consciousness. Indeed, while the average doctor would have trouble defining consciousness, we are pretty good at gauging its loss: the Glasgow Coma Scale, with its measures of eye, verbal, and motor responses, is widely used by neurologists.

There are so many ways that the body can go wrong. Cancer doctors regularly deal with altered consciousness. Sometimes it's a brain metastasis causing an epileptic fit, the electric spasm spreading through the brain, shutting off consciousness, the brain then rebooting like some errant computer. Sometimes it has been a drug effect: too much of this sedative or that chemotherapeutic. All too often it has been the end result of liver failure, the body's metabolites reaching toxic levels, the patient slipping off into that final sleep from which none awake.

I remember (I am conscious of) standing by my father's bed as he died. In his case it was hypoxia that eliminated consciousness, aided by morphine sulfate.

He had metastatic prostate cancer, his bones riddled with castrate-resistant, taxane-resistant, agony-inducing disease. He had been fading for some time, the cancer gradually robbing him of independence, of energy, and of any realistic hope. I had visited 2 weeks before for his wedding anniversary, then gone back home to see to my patients. It had been a sad visit. My brother asked me how long I thought dad had to live. Two weeks, I said. Probably not more. Sometimes we know too much.

The proximate cause of his dying was by a pulmonary embolus. He had a deep venous thrombosis in his left leg nearly a year before, abetted by a long drive from Madison, Wis., to Bonita Springs, Fla. My dad was ever an impatient driver, keen to get from point A to point B in the shortest time possible. He had not stopped a second longer than necessary, had not gotten out of the car to walk around, and the result was that he spent the last 10 months of his life on warfarin. So, the call from my brother, announcing that dad had a pulmonary embolus and was in the hospital dying came as no particular surprise.

I was in Indiana at the time, my parents in Wisconsin. I got the message in the middle of my Tuesday outpatient clinic. I called a colleague for coverage (thanks, Kathy, I still appreciate it), left work, got in my car, and drove straight to Madison.

My father was a religious man, far more so than his son, and not afraid of death. But he fought for life. He was not impatient to see what was on the other side. The day he died, he asked his oncologist whether there were any clinical trials he might enter. This was the late '90s, and anti-angiogenic therapy was all the rage, and the University of Wisconsin was scheduled to be one of the first sites for a phase I trial of endostatin, the drug a certain Nobel Laureate famously said was going to cure cancer within 2 years. My dad had told me, more than once, that if only he could hang on long enough he might yet beat the disease that inexorably consumed him.

I know, optimism bias. His performance status was such that no clinical trial in the land would have had him, and both I and his oncologist told him so, months before he lay on his deathbed. But he was a fighter, and though things were hopeless he never gave up.

When I got to the hospital, dad was severely short of breath, hyperventilating and clearly dying, and his oncologist did what kind oncologists do in such a setting: he turned up the oxygen and turned up the morphine. My dad had drifted in and out of an opiate haze for weeks, one minute drowsy, the next alert. But now he was mostly awake, conscious almost to the end.

In the last few minutes, something odd happened. At least it seemed odd to me then, and still does now. He opened his eyes, and they darted around the room, never resting for more than a second or two on any spot. It was disconcerting. Every now and then they would touch on my face, pause briefly, and move on. I had the feeling he was looking for something, something unobtainable, something…not there.

Was that the last flicker of consciousness, or just a dying brain's random electrical impulses? I'll never know. But then it was over, his consciousness utterly gone.

We speak of the soul fleeing the body, and perhaps that happened too, though that is a matter of belief rather than of science. But consciousness, at least to the extent we understand it, involves massive parallel processing of information via widely dispersed neural networks, a thoroughly natural electrochemical process, but also a highly fragile, easily disrupted one. Turn off the lights and the signaling goes away, and with it consciousness.

Are gliomas conscious? A very strange thought: could brain tumors take part in the conscious process, act as part of the global neuronal workspace? It sounds like something out of a horror story. Brain metastases certainly affect conscious function all the time. My Uncle John's smoking-induced lung cancer, upon spreading to his brain, turned that calm, church-going Baptist into an irritable spewer of obscenities. But that was loss of function, disinhibition due to frontal lobe damage. I don't think small cell lung cancer is capable of demonic possession.

The breast cancer doctor in me thinks of a well-differentiated tubular adenocarcinoma of the breast, where the cancer does its best to act like a milk duct. Could a well-differentiated brain tumor have analogous functionality, pretending conscious connectivity? Unsurprisingly, the medical literature contains no hint of such capability, and frankly I'm happy for that: it is a creepy thought, a brain hijacked by something malignant, with malignant consequences.

Charles Whitman, the 1966 Texas Tower shooter who killed 17 people and wounded 96 in America's first mass shooting—back when such events were rare—knew that something was wrong. He was, he wrote in his suicide note, the "victim of many unusual and irrational thoughts. These thoughts constantly recur, and it requires a tremendous mental effort to concentrate on useful and progressive tasks."

He requested that an autopsy be performed after his death. A pecan-sized mass, later ruled to be a glioblastoma multiforme, was discovered. Neurologists argued then, and ever since, whether it was a contributing factor in the massacre. Hard to say. But I doubt the glioma was consciously altering Whitman's consciousness.

Great evil doesn't require a physiologic explanation, though that might give us some comfort, some belief that we can explain and therefore control. We're quite good at hijacking consciousness: addictive drugs, paranoid politics, and fanatical religion being prominent examples. So leave glioma mind control to science fiction, please.

I'll stick with that old black Ford, and the comforting voices of my parents sitting in the front seat. It's a pleasant memory.

Monday, May 21, 2018

Oncology Times is 40 years old this year, a healthy middle age for a print journal devoted to a medical specialty. I started reading it as an Assistant Professor, and enjoyed it for its ability to provide an overview of my chosen profession, as I still do. I read the New England Journal of Medicine, and Nature, and the JCO, each in its own way valuable, each serving a somewhat separate purpose. I have always found Oncology Times useful for taking the pulse of my profession, and for filling me in on advances in diseases I don't see in my clinic. And yes, for the gossip—pardon me, the news—about my colleagues around the country.

I asked our editorial staff to send me the oldest edition they had, so that I might get some sense of how things have changed. The journal has moved about over time, and in those moves, apparently older issues were misplaced. The oldest issues they could find were from 1989, already—at Volume 11—a well-established eyewitness to the world of cancer. I'm sure that somewhere, in the dusty stacks of some medical library, Volume 1 exists.

Or maybe not. Perhaps the first 10 volumes have ceased to exist. In our ever-expanding digital universe, we often catch only brief glimpses of the early universe. Many journals ceased to exist before the internet became the ubiquitous source of knowledge, and as such to most of the current world never existed. Those journals that failed to digitize their early years have also, for practical purposes, eliminated those years from the global consciousness. And given how journals come and go, how long before even many of today's works disappear, their servers no longer maintained by disinterested or extinct publishers?

But enough philosophical maunderings. What did 1989 look like to the Oncology Times?

What impresses, and what I forgot, was how much the period was tinged with AIDS. The entire decade, in fact, was the decade of AIDS in oncology, with spillover into the '90s. Prior to the control of HIV with HAART regimens, AIDS-related malignancy was a growth industry for cancer doctors.

On the very first page of Issue 1, one sees an article devoted to AIDS-related Kaposi's sarcoma, treated with alpha interferon. Subsequent articles discuss the use of MRI for brain infections in AIDS, the WHO global AIDS program, CD4 as a decoy for HIV, GM-CSF for neutropenia in AIDS patients, AIDS-related lymphomas, AIDS vaccine research, and that's just through June of 1989. Every issue had a page devoted to "AIDS Briefs." Oncology Times still occasionally discusses AIDS-related cancers, but they have become rarities, not the career-builders and (increasingly) life-enders they were in that awful decade.

Though I've always been a breast cancer doctor, there was a brief period where I treated patients with Kaposi's sarcoma, though I was never a true AIDS-focused doctor. What I remember most from that era was the story of Ryan White. My current fellows probably don't know that name. Ryan White was a teenager from Kokomo, Indiana, a little north and east of Indianapolis. He had received a tainted blood transfusion for his hemophilia, and then was diagnosed with AIDS late in 1994. He was, shall we say, treated poorly by the good citizens of Kokomo, who banned him from public school and generally abused him with a long litany of indignities. He became a national cause célèbre, the face of AIDS. He lived, and died, bravely.

I would occasionally see him on the IU Medical School campus, where he received much of his treatment and where he died in 1990, just a few years short of HAART and the transformation it created. I have had friends and colleagues with hemophilia, and that period was absolutely terrifying for them. After Ryan White died, the U.S. Congress passed the Ryan White CARE Act to provide health care funding for AIDS patients. Anyone who doubts the reality of medical progress need only remember AIDS in 1989.

And, of course, AIDS-related malignancies were not the only cancer problems on the rise in 1989. Several articles discussing the rising tide of lung cancer deaths, the inadequacy of therapy for the disease, and the need for greater preventive measures. A guest editorial by William Tipping of the ACS, "Taking Tobacco's Measure," is a reminder of what we have accomplished in the smoking cessation arena. In 1989, Congress was voting on legislation limiting smoking on flights greater than 2 hours, almost unimaginable today. The airlines were balking.

On a lighter note, one of the pleasures of reviewing old issues of the Oncology Times is the opportunity to visit old friends. I hate my old pictures. I have never been even minimally photogenic, or maybe I just really look that ugly. I suspect, perusing Volume 11, that some of my colleagues share this statement. There were a lot of really funny-looking moustaches that my friends (I will not name/shame them) no longer wear. And my generation was so young then!

And the older generation? There were giants in those days, and many made it into Oncology Times that year: I see pictures of Bob Young (then still young and just-appointed president of Fox Chase), Bernie Fisher, Larry Einhorn, B.J. Kennedy, Richard Peto, Janet Rowley, Peter Nowell, Syd Salmon, Josh Fidler, and many others. Many of these have passed from the scene, and many are only remembered by aging oncologists soon to retire. We are a field strangely uninterested in our own history, but reading Volume 11 is a reminder, not only of how far we have come, but of the visionaries who brought us to where we are today.

The drug picture was also quite interesting. You see this primarily through the ads. Oncology Times, then and now, survives on advertising revenues, and ads are a great place to look at new drugs. As a breast cancer doc, I see ads for tamoxifen: while the drug had already been around for a decade; adjuvant hormonal therapy was still relatively new. But no HER2-targeted drugs, though there is an article on HER2, primarily as a potential prognostic factor. Trastuzumab was not yet even a twinkle in Genentech's eye, and most of the drugs I use today in the metastatic setting, even the chemotherapeutics, are missing. From a chemotherapy standpoint, a full-page advertisement for Adriamycin bragged "ADRIAMYCIN IS NOW 97% PURE," which says all you need to know about the relative therapeutic poverty of the era.

Today, oncologists can draw on an immense number of agents. My boss, a cardiologist, tells me that most of the drugs he uses are off-patent, which is a foreign thought to today's cancer doctors and the source of both our patients' hopes and economic woes. But in 1989, the biotech revolution was in its infancy, tamoxifen was pretty much the only targeted therapy for cancer, there were no "ibs," no "mabs," nothing we currently take for granted. Even modern supportive care drugs have not yet entered practice: the anti-emetics ads are for Marinol and Compazine.

Oncology Times had a wonderful business reporter at the time, named Robert Teitelman, whose beat was the biotech business. His articles discuss companies I had long forgotten, such as Chiron, Integrated Genetics, Hybritech, NeoRx, and Centocor. Then, as now, the big fish were busy eating up the minnows, and most of these names disappeared into the welcoming arms of some larger company. What differed was the cost of the buy-outs, in the tens of millions as opposed to today's billions. There are hints of what's to come, with a scramble to produce monoclonal antibodies, and lymphoma mentioned as a prominent target, as well as IDEC as a company interested in the area, though no rituximab is yet on the scene. Oh, for a time machine and access to a stockbroker (you couldn't yet order your shares online).

There are other promising notes in that year's issues. The 1989 Nobel Prize for Physiology or Medicine went to UCSF's Michael Bishop and Harold Varmus, for their demonstration that the Rous sarcoma virus was in fact a mutated normal cellular gene. This discovery led to the oncogene revolution, with far-reaching effects for diagnosis and treatment of human cancer. It was clear, even then, that the way forward would require the application of that biologic evolution to the clinic, though it was also evident that the path upward was difficult, twisty, and covered with obscuring undergrowth.

Some things haven't changed. The November issue reports a survey of oncologist's attitudes towards their specialty. Oncologists in 1989 stressed about their patient's high mortality rates, and their own long hours and inadequate work-life balance. But they love their patients, and obtain personal satisfaction from offering them help, even if that help paled in comparison to what we can offer today. Other articles discussed issues we still face: the cost of quality care (if only we knew then how cheap things actually were, and how expensive they were destined to be), nursing burnout and retention, health disparities related to access, race and poverty. In other words, plus ça change, plus c'est la même chose. But the progress is real. I wonder what Volume 80 will say? I hope there is no Volume 80, or no need for it. But until then, Oncology Times will still have a proper place. Read on, for there are wonders ahead.