One of my favorite television shows right now is The Knick, as I described before in a post about medical history. To give you an idea of how much I’m into The Knick, I’ll tell you that I signed up for Cinemax for three months just for that one show. (After its second season finale airs next Friday, I’ll drop Cinemax until next fall.) The reason why I’m bringing up The Knick (besides I love the show and need to bring it up at least once a year) is because an article by Malcolm Gladwell published earlier this week in The New Yorker entitled Tough Medicine, which is a commentary based on a new book on cancer by a veritable god of cancer research, Vincent T. DeVita, Jr., immediately resonated with a storyline in this season of The Knick. I haven’t yet read The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable–and How We Can Get There by Vincent T. DeVita and Elizabeth DeVita-Raeburn, but I would like to. I can tell, though, that there will be parts of the book I find annoying, at least if Gladwell’s take on the book is accurate as he semi-approvingly describes DeVita as railing against the cautiousness and incremental nature of today’s cancer research. On the other hand, the article does conclude with Gladwell demonstrating a better understanding of the disadvantages of what DeVita is proposing than it seems that he will in the beginning. In fact, it is Gladwell who seemingly ends up being more reasonable than his subject, although he does appear share DeVita’s apparent assumption that potentially all cancer patients are savable if only we try hard enough.
The Brave Maverick Doctor versus the clinician-scientist
Here’s where my reference to The Knick comes in. (Because it seems mandatory these days, I’ll issue a spoiler alert right now. Skip to the next section if you don’t want to be exposed to major plot points from the show.) The Knick is a TV series set in the fictional Knickerbocker Hospital in lower Manhattan and takes place more than a century ago, the first in 1900, the second in 1901. Its main character, Dr. John Thackery (brilliantly portrayed by Clive Owen) is a surgeon clearly patterned on one of the veritable gods of American surgery, William Stewart Halsted, whose contributions to surgery, including blood transfusions, sterile surgical gloves, local anesthesia, an emphasis on the delicate handling of tissue, cancer surgery, and the surgical residency program, are legendary. He was also a cocaine and morphine addict, but managed to function well in spite of his addictions. Thackery is also an addict, but doesn’t function nearly as well.
The fictional Dr. Thackery is a type of doctor to whom I’ve referred as the Maverick Doctor, or Brave Maverick Doctor when I’m in a sarcastic mood. Such doctors can be bold, reckless even. They believe in their own rightness, thinking that their training as physicians should be enough for society to trust their judgment to do what they believe to be right and bristle at anything they view as constraining their freedom of medical judgment in any way, such as evidence-based treatment guidelines. When they’re right, as, for example, William Halsted and Vincent DeVita frequently were, they can push the envelope of medicine faster than anyone. There’s a very good reason why, for example, DeVita is one one of editors of the main textbook of oncology owned by most oncologists, myself included. Unfortunately,when Brave Maverick Doctors are wrong (the far more frequent situation), as, for example, Stanislaw Burzynski is wrong, they are frequently very, very wrong and can do great harm. Not surprisingly, there is a disturbingly high percentage of quacks among Brave Maverick Doctors. Think Mark Geier. Think Rashid Buttar. Think Andrew Wakefield. You get the idea. Indeed, there is a whole medical organization dedicated to Brave Maverick Doctors, the American Association of Physicians and Surgeons (AAPS).
Relevant to DeVita’s book and Gladwell’s article, one of the central themes of The Knick is the conflict between the innovation of Brave Maverick Doctors and its inherent risk. This conflict is embodied in the character of Thackery, who is often bold to the point of recklessness in his pursuit of curing disease. On the other side, the slow, methodical accumulation of scientific knowledge is represented by Dr. Levi Zinberg at Mt. Sinai Hospital. Thackery is all about trying new things, almost regardless of the cost or risk, while Zinberg is all about collaboration and the careful, incremental, scientific advancement of medicine. In the first season, for example, Thackery comes to view Zinberg as a competitor, even going so far as to become obsessed with identifying different blood types before Zinberg does, after having been informed that that’s what Zinberg was working on. Zinberg, for his part, offers collaboration leading to the slow, systematic accumulation of knowledge. He even shares his laboratory notes with one of Thackery’s junior surgeons, Bertram Chickering, Jr., to show his good faith, telling Chickering to feel free to show the notes to Thackery.
In the second season, this conflict is even more prominent. In episode 3 this season, The Best with the Best to Get the Best (whose title, ironically, is about eugenics, which makes its first appearance in the series here), for personal reasons Chickering decides to leave the Knick and take a position at Mt. Sinai working for Zinberg. There, his experience with Thackery comes into immediate conflict with the way things are done at Mt. Sinai, where he is disappointed when Zinberg assigns him a laboratory project working with a new gland extract (adrenaline) instead of letting him operate right away. When Chickering suggests accelerating the testing of the new gland extract in animals from mice to larger animals or even humans, he is told in no uncertain terms,”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”
Dr. Bertrand Chickering, Jr. (right) runs into a little conflict by wanting to move too fast for his new team and is told, ”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”
This conflict comes to a head when Chickering’s mother is diagnosed with inoperable laryngeal cancer. He tells Zinberg of his mother’s condition and that he is determined to seek out new experimental procedures to save her life. Zinberg replies by cautioning him not to let his emotions get the better of him. This leads him to seek out Dr. Algernon Edwards, a brilliant African-American surgeon hired early in the first season by the Knick’s board of directors over Thackery’s objections (which were based on racism, of course) who had ultimately won Thackery’s respect. Edwards tells Chickering of a paper by Pierre Curie, and says he can translate it from French if Bertie locates a copy, which he does. The procedure involves injecting the tumor with mercury and zinc and then zapping it with electricity. This leads to an episode entitled, appropriately enough, There Are Rules, where Chickering, breaking the rules, persuades Edwards to help him, saying, “I don’t have the luxury of two years of study.” It is about as succinct an expression of the inherent conflict in medical research between risk and careful scientific study as you’ll ever see.
And help him Edwards does. The two operate on Chickering’s mother at Mt. Sinai in secret, with Chickering’s father in the room, unable to watch. Not surprisingly, the surgery does not go well. The tumor does not soften as predicted, and the two surgeons get into bleeding and do damage to Mrs. Chickering’s airway while trying to separate the tumor from surrounding structures. They are also discovered by a janitor, who informs Zinberg, who bursts in a few minutes later demanding to know what the hell is going on. To his credit, when Zinberg sees the situation, he refrains from further scolding and leaps in to help as much as he can. Unfortunately, they can’t save Mrs. Chickering, who dies on the table. Thus ends Chickering’s tenure at Mt. Sinai. He resigns before Zinberg can fire him; not surprisingly he winds up back at the Knick with Thackery, who has actually become slightly less reckless.
This fundamental conflict between careful, slow scientific progress and the need to do something for patients who are suffering now and going to die soon is a theme Gladwell revisits in his article. Of course, most clinical researchers are not a Dr. Thackery or a Dr. Zinberg, who really are archetypes more than anything else. Most physician-scientists and clinical researchers fall somewhere in between these extremes. What seems to bother Gladwell and Dr. DeVita is that over the last three decades the balance in medicine has clearly moved away from the Thackerys and towards the Zinbergs, which leads DeVita to make the same sorts of misguided arguments that I’d discussed being made for right-to-try laws, the Saatchi bill, and the 21st Century Cures Act, all of which seek to remove patient protections in the name of letting Maverick Doctors “innovate” more.
Brave Maverick Oncologists and the wild, wild West of the 1960s
When I referred to Vincent DeVita as a “god” of oncology, I was only exaggerating slightly. If you don’t believe me, go back and read a post I wrote two years ago that uses one of DeVita’s review articles as a jumping off point to discuss how chemotherapy went from a near-fringe idea to being validated as a successful treatment for a number of cancers. It’s a good overview of the history of chemotherapy, a history that DeVita lived right in the middle of and whose success he was very much a part of. Now 80 years old, DeVita uses his book to look back at the history of cancer chemotherapy, and the anecdote that Gladwell chooses to start his article is very telling:
In the fall of 1963, not long after Vincent T. DeVita, Jr., joined the National Cancer Institute as a clinical associate, he and his wife were invited to a co-worker’s party. At the door, one of the institute’s most brilliant researchers, Emil Freireich, presented them with overflowing Martinis. The head of the medical branch, Tom Frei, strode across the room with a lab technician flung over his shoulder, legs kicking and her skirt over her head. DeVita, shocked, tried to hide in a corner. But some time later the N.C.I.’s clinical director, Nathaniel Berlin, frantically waved him over. Freireich, six feet four and built like a lineman, had passed out in the bathtub. Berlin needed help moving him. “Together, we pulled him up, threw his arms over our shoulders, and dragged him out through the party,” DeVita writes, in his memoir, “The Death of Cancer” (Sarah Crichton Books). “Out front, Freireich’s wife, Deanie, sat behind the wheel of their car. We tossed Freireich in the backseat and slammed the door.”
Half a century ago, the N.C.I. was a very different place. It was dingy and underfunded—a fraction of its current size—and home to a raw and unruly medical staff. The orthodoxy of the time was that cancer was a death sentence: the tumor could be treated with surgery or radiation, in order to buy some time, and the patient’s inevitable decline could be eased through medicine, and that was it. At the N.C.I., however, an insurgent group led by Frei and Freireich believed that if cancer drugs were used in extremely large doses, and in multiple combinations and repeated cycles, the cancer could be beaten. “I wasn’t sure if these scientists were maniacs or geniuses,” DeVita writes. But, as he worked with Freireich on the N.C.I.’s childhood-leukemia ward—and saw the fruits of the first experiments using combination chemotherapy—he became a convert.
You get the idea. Back in 1963, men were men, women were women, and the sheep ran scared. Or something. Maybe it was Mad Men, but with oncologists and cancer researchers instead of advertising executives. Or maybe the NCI was the wild, wild West, populated by nothing but Maverick Doctors. As I will discuss, the wild frontier turns out to be a very good metaphor for cancer research as practiced 50 years ago, at least in terms of the attitudes of the physicians at the forefront back then compared to the way things are done now.
Having established early NCI of the early 1960s as the wild West, Maverick doctor bona fides of the era, Gladwell next relates anecdotes from DeVita’s book in which a Maverick doctor shows those cautious, pointy-headed professors how curing cancer is done, starting with one of DeVita’s own accomplishments when he decided to try to replicate Frei and Freirich’s success with childhood leukemia in an adult malignancy. Back in the early 1960s, Hodgkin’s disease, too, was also a virtual death sentence, with very little that doctors could do to save the lives of patients diagnosed with the disease. Over a few beers one night, DeVita and a colleague named Jack Moxley mapped out a protocol based on what Frei and Freireich were doing with leukemia. Because of the ability of cancer cells to mutate and develop resistance under the selective pressure of chemotherapy, they estimated that they needed four drugs, each working through a different mechanism, so that the cells that survived one wave would be killed by the next. They then plotted how often the drugs could be given and how high the doses would need to be. Obviously, the doses needed to be high enough to kill the cancer cells but not so high that the patient died. Ultimately they settled on a regimen called MOMP: three eleven-day rounds of nitrogen mustard, Oncovin (a brand of vincristine), methotrexate, and prednisone, interspersed with ten-day recovery cycles.
This story is the very essence of science-based medicine combined with “maverick-y-ness. Here, two oncology fellows carefully examined the medical literature regarding chemotherapy drugs and what was known about the biology of Hodgkins’ lymphoma at the time and came up with what seemed to be a reasonable combination of drugs. It’s not something that could be done today in the same way, but as I will explain, contrary to what DeVita and Gladwell seem to think, that’s not a bad thing. In the meantime, let’s look at what happened:
“The side effects were almost immediate,” DeVita writes:
The sound of vomiting could be heard along the hallway. Night after night, Moxley and I paced outside the rooms of our patients, fearful of what might happen. Over the weeks that followed, they lost weight and grew listless, and their platelet counts sank lower and lower to dangerous levels.
Then came the surprise. Twelve of the fourteen patients in the initial trial went into remission—and nine stayed there as the months passed. In most cases, the tumors disappeared entirely, something that had never before been seen in the treatment of solid tumors. In the spring of 1965, DeVita went to Philadelphia to present the results to the annual meeting of the American Association for Cancer Research. He stood up before the crowd and ran triumphantly through the data: “ ‘Our patients were, therefore,’ I said, savoring the dramatic conclusion, ‘in complete remission.’ ”What happened? An illustrious cancer expert named David Karnofsky made a narrow point about the appropriateness of the term “complete remission.” After that, nothing: “There were a few perfunctory questions about the severity of the side effects. But that was it.” History had been made in the world of cancer treatment, and no one seemed to care.
Why did DeVita’s work receive such a lukewarm reception? It’s hard to say. It could well have been the natural reticence and skepticism that scientists exercise upon hearing radical new results. It could well have been that the audience thought the data too good to be true. Whatever the reason, Gladwell next discusses the next stage of DeVita’s career, when after finishing his fellowship at the NCI he went to Yale to do another year of residency before coming back to the NCI. A stronger echo of Dr. Chickering’s experience leaving the Knick and taking a position at Mt. Sinai would be hard to imagine:
When his first go-round as a clinical associate at the N.C.I. was up, DeVita took a post as a resident at Yale. At what was supposed to be a world-class hospital, he discovered that the standard of care for many cancers was woefully backward. Freireich had taught DeVita to treat Pseudomonas meningitis in leukemia patients by injecting an antibiotic directly into the spinal column—even though the drug’s label warned against that method of administration. That was the only way, Freireich believed, to get the drug past the blood-brain barrier. At Yale, DeVita writes, “you just didn’t do that kind of thing. As a result, I watched leukemic patients die.” Leukemia patients also sometimes came down with lobar pneumonia. Conventional wisdom held that that ought to be treated with antibiotics. But N.C.I. researchers had figured out that the disease was actually a fungal infection, and had to be treated with a different class of drug. “When I saw this condition in patients with leukemia and pointed it out to the chief of infectious diseases at Yale, he didn’t believe me—even when the lab tests proved my point,” DeVita continues. More patients died. Leukemia patients on chemotherapy needed platelets for blood transfusions. But DeVita’s superiors at Yale insisted there was no evidence that transfusions made a difference, despite the fact that Freireich had already proved that they did. “Ergo, at Yale,” DeVita says, “I watched patients bleed to death.”
Elsewhere, DeVita relates how he had originally wanted to do a fellowship at Yale too but decided to come back to the NCI after a year because of his experiences at Yale.
It’s hard to judge this story without knowing a bit more, but notice how DeVita said that Freirich had taught him to treat Pseudomonas meningitis with intrathecal antibiotics. Had he yet published a convincing clinical study showing that intrathecal antibiotics worked better? I searched for Freireich’s publications on Pseudomonas infections from the 1960s; all I could find was an analysis of 54 episodes of multiple organism sepsis in leukemia patients from 1965, which isn’t applicable to the problem. A search for Freirich’s name and just “meningitis” only revealed this case report from 1968 on Listeria monocytogenes meningitis. In other words, as far as I can ascertain, Freireich had apparently not published his experience with the use of intrathecal antibiotics for meningitis in leukemia patients at the time DeVita was at Yale. Similarly, I was not able to find papers by Freireich on fungal infections before 1968. So why on earth would the doctors at Yale believe DeVita? Why should they have? If it’s not published, then why would they do it? On the other hand, Freireich had published several papers on the effectiveness of transfusions by the late 1960s, one in the New England Journal of Medicine in 1959.
Whether or not he was off base criticizing his colleagues at Yale in the late 1960s, DeVita does note something that I’ve noted myself, as have many others, namely that new ideas are often resisted and that clinical practice doesn’t always change. He noted that he couldn’t do a combination-chemotherapy trial in the US because it went against the grain at the time, necessitating doing it overseas. He also cites the example of Bernie Fisher, who had shown that there was no difference in survival in breast cancer between radical mastectomy and much less invasive breast-conserving surgery followed by radiation therapy, and how he had had difficulty enrolling patients to his studies because of resistance from surgeons.
What DeVita neglects to note is that eventually data did win out, and our practice changed. Indeed, I myself have never even done a radical mastectomy because the procedure had been obsolete years before I did my surgical residency. Heck, my practice has changed radically, in response to clinical trials, just since I first became an attending in 1999. As I like to point out, change in science-based medicine is messy. It often takes more time than we think it should, particularly in retrospect. But eventually we do change practice in response to data and science. At the heart of this change, the question is always: How much new evidence is required before a critical mass of physicians are convinced to change practice? Not all conservatism in medicine is bad. One need only point to the debacle that resulted from the much too rapid adoption of high dose chemotherapy and bone marrow transplantation for advanced breast cancer that became popular in the 1990s, only to be shown to do no good and cause a lot of harm when decent randomized clinical trials were done.
Innovation versus practice guidelines
A second key anecdote from DeVita’s book related by Gladwell involves DeVita’s experience with how a new regimen that he developed was altered as it spread from the NCI to other cancer centers, in this case Memorial Sloan-Kettering Cancer Center (MSKCC). Basically, over the next few years, DeVita and colleagues refined the MOMP regimen, which became MOPP: two full doses of nitrogen mustard and vincristine on the first and the eighth days, and daily doses of procarbazine and prednisone for fourteen days, followed by two weeks of rest. The results of a second trial, published in 1970, showed MOPP to be superior to MOMP.
What puzzled DeVita was how tepid the response was at MSKCC when he presented his work there. Indeed, oncologist after oncologist there told him MOPP “didn’t work.” Why was that? Ironically enough, it was the product of the very same sort of tinkering that DeVita had used seven years earlier to develop MOMP:
Baffled, he asked one of the hospital’s leading oncologists, Barney Clarkson, to explain exactly how he was administering the MOPP protocol. Clarkson answered that he and his colleagues had decided to swap the nitrogen mustard in DeVita’s formula for a drug called thiotepa. This was a compound they had developed in-house at Memorial Sloan Kettering and felt partial to. So MOPP was now TOPP. DeVita writes:
They’d also cut the dose of procarbazine in half, because it made patients nauseous. And they’d reduced the dose of vincristine drastically because of the risk of nerve damage. They’d also added, at a minimum, an extra two weeks between cycles so that patients would have fully recovered from the toxic effects of the prior dose before they got the next. They gave no thought to the fact that the tumor would have been back on its feet by then, too, apparently.
These alterations had not been tested or formally compared with DeVita’s original formula. They were simply what the oncologists at Memorial Sloan Kettering felt made more sense. After an hour, DeVita had had enough:
“Why in God’s name have you done this?” he asked.
A voice piped up from the audience. “Well, Vince, most of our patients come to us on the subway, and we don’t want them to vomit on the way home.”
Here were physicians at one of the world’s greatest cancer hospitals denying their patients a potentially life-saving treatment because their way felt better.
So basically, the doctors at MSKCC had altered the protocol, and the resultant protocol, TOPP, didn’t work. What would have been appropriate, if the oncologists at MSKCC really thought their protocol was an improvement, would have been to do a clinical trial comparing MOPP to TOPP head to head, but they didn’t do that. They just changed DeVita’s protocol as they saw fit and started using it. For them to conclude that TOPP didn’t work, it must have been very obviously different from the results reported by DeVita with MOPP, because there was no control group and no clinical trial. Worse, if DeVita’s account is to be believed, the oncologists at MSKCC didn’t even differentiate their new protocol from DeVita’s original protocol or figure out that the reason that their protocol didn’t work was because of their alterations.
One might think that this sort of experimentation would indicate that perhaps there should be some clinical guidelines that made sure that MOPP, which had been validated as effective in clinical trials, should be administered the same way, but that’s exactly the opposite of what DeVita argues, according to Gladwell:
But here “The Death of Cancer” takes an unexpected turn. DeVita doesn’t think his experience with the stubborn physicians at Memorial Sloan Kettering or at Yale justifies greater standardization. He is wary of too many scripts and guidelines. What made the extraordinary progress against cancer at the N.C.I. during the nineteen-sixties and seventies possible, in his view, was the absence of rules.
And:
Clinical progress against a disease as wily and dimly understood as cancer, DeVita argues, happens when doctors have the freedom to try unorthodox things—and he worries that we have lost sight of that fact.
Where have we heard these arguments before? Oh, yes. I remember. They’re the same arguments made by proponents of the Saatchi Bill and the misguided 21st Century Cures Act. The central idea behind all of these policy ideas is that we somehow have to “free” doctors and researchers to “innovate,” rather than “shackling” them. The impetus for these ideas is, in essence, worshiping at the altar of the cult of the Brave Maverick Doctor. It is the Great Man (or Woman) theory of the history of medicine, in which breakthroughs come not so much because of the gradual accretion of knowledge, with each new scientific finding building on what has been discovered before, but because of singular individuals with the vision and the bravery to see what needs to be done and the cleverness, intelligence, and will to do it.
DeVita vs the FDA
Gladwell notes that the angriest part of DeVita’s book is his chapter about the FDA, where he argues that the FDA has somehow fundamentally misunderstood innovation. I rather suspect a lot of DeVita’s hostility comes from two experiences he had in his life. First, he describes a prolonged battle to save his friend Lee, who developed advanced prostate cancer. DeVita kept pushing to get him into clinical trial after clinical trial, to get experimental therapies off protocol, and basically to try anything that could be tried, ending when he couldn’t get his friend an experimental drug called abiraterone. His friend died He later learned that abiraterone was so effective that the clinical trial was halted early and now clearly believes that he could have saved him, even though there is no cure for advanced prostate cancer. (Abiraterone significantly prolongs life, but is not a cure.) Even so, abiraterone was no cure. Another incident is that DeVita, ironically enough, was the father of the Ted DeVita, the “boy in the bubble,” who developed aplastic anemia and lived well over eight years in a plastic bubble before succumbing.
Specifically, he objects to the FDA’s mandate to require that all new approved drugs be safe and efficacious, pointing out that this “gatekeeping” function of the FDA can hinder progress. I’ll have to wait to read the book to see if DeVita’s argument is more compelling than how Gladwell represents it, but I was underwhelmed, as not a single example of how “progress” had been hindered was provided, only hypothetical examples. In one, he suggests that cancer is like a door with three locks, each with a different key. If a drug “opens the first lock,” it would be a breakthrough but wouldn’t cure the cancer by itself. So DeVita asks:
So how do you get it through a trial that requires proof of efficacy—especially if you don’t yet know what the right keys for the two remaining locks are? Since cancer comes in a dizzying variety of types and subtypes, each with its own molecular profile, we want researchers to be free to experiment with different combinations of keys.
The problem with this analogy is that it is disappointingly simplistic given who is making it and that the time to work out the preliminary answer to this question is in preclinical research leading to the development of this drug and others, not in human beings. Moroever, as represented by Gladwell, this argument completely ignores the incredible genetic heterogeneity of even a single cancer, where different cells, even in the same tumor, might have different combinations of these locks. He also criticizes the FDA for approving drugs for very specific indications, including specific cancers and even specific stages of cancers, complaining, “The vital insight gained by using an approved drug in a different way for a different tumor has been lost.” No, it has not. In this age of precision medicine based on genomics, if anything, we’re becoming more open to trying drugs designed for one tumor in another tumor based on the genetic abnormality it targets rather than the tissue of origin of the tumor. The FDA is struggling, as we all are, with the question of how to target therapy to the individual characteristics of the tumor. New forms of clinical trials are being tested. New regulatory frameworks are being developed.
To his credit, Gladwell points out exactly what’s wrong with DeVita’s argument for more freedom to tinker, specifically the paradox at the heart of it. First, he notes that the breakthroughs at the NCI in the 1960s and 1970s were the product of a freewheeling intellectual climate and a relative lack of rules over what could and could not be done in clinical trials. Indeed, it’s quite true that no one could do now what DeVita did 52 years ago. At the same time, it was that very same climate that allowed the oncologists at MSKCC muck up DeVita’s effective chemotherapy regimen by turning MOPP into TOPP. The problem with such a freewheeling atmosphere without rules is that, for it to be a net benefit, there have to be more doctors like Emil Freireich and Vincent DeVita than there are like Barney Clarkson, as Gladwell notes. Personally, having been in medicine in one form or another for 30 years now, I am not nearly so confident that there aren’t a lot more Barney Clarksons than Vincent DeVitas. In fact, I’m quite sure that there are and that, contrary to DeVita’s claims that an extra 100,000 more patients a year could be cured if we just used all the wonderful drugs out there to their fullest potential, opening medical practice and research to the sort of “innovation” DeVita proposes would end up harming far more patients than it would ever help.
Let’s just put it this way. By DeVita’s definition, Stanislaw Burzynski is “innovating” with his “make it up as you go along” form of “personalized gene-targeted” cancer therapy combined with his antineoplastons. After all, “innovation” is very difficult to identify, except in retrospect, after we know what works and what doesn’t, who is a Stanislaw Burzynski-style maverick and who is a Vincent DeVita-style maverick.
The problem with mavericks and nostalgia
‘Cause the good ole days weren’t
Always good
And tomorrow ain’t as bad as it seems
DeVita’s complaints about medicine are not uncommon. I tend to hear complaints like his from (mostly) an older generation of physicians who came of age in terms of their medical career during times when physician autonomy was perceived to be much closer to absolute and constraints on doing research less onerous, in other words, in a more freewheeling “wild West” sort of atmosphere. Given that, I can’t help but think that there is more than a little nostalgia, a pining for the “good old days,” in DeVita’s book. I also can’t help but wonder if Gladwell was rather selective in his quoting of DeVita, given that in an NPR interview just one month ago promoting his book, DeVita said very little that was so critical of the state of cancer research.
Be that as it may, I tend to view new fields of medical research as being rather like the American frontier. The first ones in are the hardiest and bravest, the ones willing to take the most risk, such as trappers and mountain men. They clear the way for the next wave, and as new arrivals keep coming, civilization intrudes. There are more and more laws and rules, and there is no longer absolute freedom. Eventually, what was once frontier is now little different from the states where all the settlers came from, and the original trailblazers have either moved on or struggle to fit in. Cancer research is rather like that. Back in its “wild West” period, because so little was known about cancer and so few effective treatments existed outside of surgery for certain specific cancers, there was an “anything goes” culture because, or so it was perceived, there was much to gain and very little to lose by trying almost anything. So men like DeVita (and, yes, unfortunately is was almost all men back then) did. Also, the less that’s known, the more variability in care is acceptable, because we don’t know what the best existing treatment is. The more we learn, the greater the risk in practicing outside of evidence-based guidelines because doing so becomes more likely to harm than help.
We are all products of our time and experiences, and DeVita is no different. He became a cancer researcher in a specific time and place, and his life experiences, particularly with his son with aplastic anemia and his friend with prostate cancer shaped his views. Think of it this way: DeVita, as brilliant as he is and as deserving as he is of all the respect he gets, was nonetheless very fortunate very early in his career. After all, his first attempt at innovation through tinkering happened to be a smashing success. There was no guarantee at the time that this would be the case. Indeed, it’s not hard to imagine an alternative history, in which his first attempt at multimodality chemotherapy was so toxic that it killed most of his patients before their cancers could or was simply ineffective and toxic. Would DeVita view giving physicians unfettered freedom to “tinker” so favorably if that had been the case? After all, in other hands, such tinkering resulted in an ineffective treatment combination.
One thing I like about The Knick is that it shows that one maverick can easily produce both outcomes: disaster and greatness. In other words, it’s a mistake to separate mavericks into Freireich-style mavericks and Clarkson-style mavericks. Any single maverick, for any given bit of “tinkering,” can produce Freireich or DeVita results or he can produce Clarkson-style results. Indeed, when Brave Maverick Surgeon John Thackery does his “tinkering,” sometimes, he’s successful, as when he successfully separates a pair of conjoined twins this season. More often, Thackery fails miserably. Two of the more dramatic failures occurred late in the first season when Thackery outright killed a girl transfusing her with his own blood based on his incorrect hypothesis of what determined different blood types and in the second season when, while trying to treat a man’s addiction by ablating part of his brain with an electrical probe, he inadvertently damaged part of the brain that resulted in a locked in patient, about as horrible an outcome as can be imagined. (If you don’t know what locked in syndrome is, read this or watch The Diving Bell and the Butterfly. It’s arguably a fate worse than death.) This season, when Chickering, following the lead of his mentor, tries an experimental treatment on his mother, disaster ensues. The converse can also happen, as in the first season when Dr. Zinberg develops the “illuminating intrascope,” which allows doctors to look inside their patients without making large incisions. (Basically, it was a precursor to what we use today as the laparoscope.) This conflict appears poised to play itself out in the season finale tonight, as the synopsis includes this: “Thackery eschews Zinberg’s (Michael Nathanson) advice at Mt. Sinai and opts for a dramatic, and risky, alternative course of action.”
Same as it ever was.
Unlike 50 (or 115) years ago, medicine today is, for better or worse, largely a “team sport.” This is particularly true when it comes to serious diseases like cancer. For instance, in my specialty, breast cancer surgery, it’s uncommon that I am the only physician involved in the care of my patients with breast disease. It happens for patients undergoing a biopsy and for patients with ductal carcinoma in situ whose tumors are hormone receptor negative and who are thus not going to benefit from estrogen-blocking therapy. Even in both of these cases, at the very least a pathologist is also involved. The care of the rest of my patients involves a combination of surgery, radiation oncology, and medical oncology.
The collaborative nature of cancer care today can be frustrating to some doctors. In addition, there is a certain type of personality that views evidence-based guidelines as “being told what to do.” It’s not hard to find these doctors; indeed, just peruse the feed for Kevin, MD, and it won’t take more than a few days for you see them, and if you peruse the AAPS Twitter feed, you’ll see them in spades. Truly, the appeal of the cult of the Brave Maverick Doctor is strong. It’s just disappointing to see a physician as eminent as Vincent DeVita worshiping at the altar of the cult of the Brave Maverick Doctor.
Few physicians are as brilliant as Dr. DeVita or Dr. Freireich, and even brilliant maverick doctors “tinkering” the way DeVita did tend to be wrong far more often than they are correct. That’s why, as The Knick puts it, there are rules. Reasonable people can disagree over how strict those rules need to be, but there have to be rules.
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One of my favorite television shows right now is The Knick, as I described before in a post about medical history. To give you an idea of how much I’m into The Knick, I’ll tell you that I signed up for Cinemax for three months just for that one show. (After its second season finale airs next Friday, I’ll drop Cinemax until next fall.) The reason why I’m bringing up The Knick (besides I love the show and need to bring it up at least once a year) is because an article by Malcolm Gladwell published earlier this week in The New Yorker entitled Tough Medicine, which is a commentary based on a new book on cancer by a veritable god of cancer research, Vincent T. DeVita, Jr., immediately resonated with a storyline in this season of The Knick. I haven’t yet read The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable–and How We Can Get There by Vincent T. DeVita and Elizabeth DeVita-Raeburn, but I would like to. I can tell, though, that there will be parts of the book I find annoying, at least if Gladwell’s take on the book is accurate as he semi-approvingly describes DeVita as railing against the cautiousness and incremental nature of today’s cancer research. On the other hand, the article does conclude with Gladwell demonstrating a better understanding of the disadvantages of what DeVita is proposing than it seems that he will in the beginning. In fact, it is Gladwell who seemingly ends up being more reasonable than his subject, although he does appear share DeVita’s apparent assumption that potentially all cancer patients are savable if only we try hard enough.
The Brave Maverick Doctor versus the clinician-scientist
Here’s where my reference to The Knick comes in. (Because it seems mandatory these days, I’ll issue a spoiler alert right now. Skip to the next section if you don’t want to be exposed to major plot points from the show.) The Knick is a TV series set in the fictional Knickerbocker Hospital in lower Manhattan and takes place more than a century ago, the first in 1900, the second in 1901. Its main character, Dr. John Thackery (brilliantly portrayed by Clive Owen) is a surgeon clearly patterned on one of the veritable gods of American surgery, William Stewart Halsted, whose contributions to surgery, including blood transfusions, sterile surgical gloves, local anesthesia, an emphasis on the delicate handling of tissue, cancer surgery, and the surgical residency program, are legendary. He was also a cocaine and morphine addict, but managed to function well in spite of his addictions. Thackery is also an addict, but doesn’t function nearly as well.
The fictional Dr. Thackery is a type of doctor to whom I’ve referred as the Maverick Doctor, or Brave Maverick Doctor when I’m in a sarcastic mood. Such doctors can be bold, reckless even. They believe in their own rightness, thinking that their training as physicians should be enough for society to trust their judgment to do what they believe to be right and bristle at anything they view as constraining their freedom of medical judgment in any way, such as evidence-based treatment guidelines. When they’re right, as, for example, William Halsted and Vincent DeVita frequently were, they can push the envelope of medicine faster than anyone. There’s a very good reason why, for example, DeVita is one one of editors of the main textbook of oncology owned by most oncologists, myself included. Unfortunately,when Brave Maverick Doctors are wrong (the far more frequent situation), as, for example, Stanislaw Burzynski is wrong, they are frequently very, very wrong and can do great harm. Not surprisingly, there is a disturbingly high percentage of quacks among Brave Maverick Doctors. Think Mark Geier. Think Rashid Buttar. Think Andrew Wakefield. You get the idea. Indeed, there is a whole medical organization dedicated to Brave Maverick Doctors, the American Association of Physicians and Surgeons (AAPS).
Relevant to DeVita’s book and Gladwell’s article, one of the central themes of The Knick is the conflict between the innovation of Brave Maverick Doctors and its inherent risk. This conflict is embodied in the character of Thackery, who is often bold to the point of recklessness in his pursuit of curing disease. On the other side, the slow, methodical accumulation of scientific knowledge is represented by Dr. Levi Zinberg at Mt. Sinai Hospital. Thackery is all about trying new things, almost regardless of the cost or risk, while Zinberg is all about collaboration and the careful, incremental, scientific advancement of medicine. In the first season, for example, Thackery comes to view Zinberg as a competitor, even going so far as to become obsessed with identifying different blood types before Zinberg does, after having been informed that that’s what Zinberg was working on. Zinberg, for his part, offers collaboration leading to the slow, systematic accumulation of knowledge. He even shares his laboratory notes with one of Thackery’s junior surgeons, Bertram Chickering, Jr., to show his good faith, telling Chickering to feel free to show the notes to Thackery.
In the second season, this conflict is even more prominent. In episode 3 this season, The Best with the Best to Get the Best (whose title, ironically, is about eugenics, which makes its first appearance in the series here), for personal reasons Chickering decides to leave the Knick and take a position at Mt. Sinai working for Zinberg. There, his experience with Thackery comes into immediate conflict with the way things are done at Mt. Sinai, where he is disappointed when Zinberg assigns him a laboratory project working with a new gland extract (adrenaline) instead of letting him operate right away. When Chickering suggests accelerating the testing of the new gland extract in animals from mice to larger animals or even humans, he is told in no uncertain terms,”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”
Dr. Bertrand Chickering, Jr. (right) runs into a little conflict by wanting to move too fast for his new team and is told, ”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”
This conflict comes to a head when Chickering’s mother is diagnosed with inoperable laryngeal cancer. He tells Zinberg of his mother’s condition and that he is determined to seek out new experimental procedures to save her life. Zinberg replies by cautioning him not to let his emotions get the better of him. This leads him to seek out Dr. Algernon Edwards, a brilliant African-American surgeon hired early in the first season by the Knick’s board of directors over Thackery’s objections (which were based on racism, of course) who had ultimately won Thackery’s respect. Edwards tells Chickering of a paper by Pierre Curie, and says he can translate it from French if Bertie locates a copy, which he does. The procedure involves injecting the tumor with mercury and zinc and then zapping it with electricity. This leads to an episode entitled, appropriately enough, There Are Rules, where Chickering, breaking the rules, persuades Edwards to help him, saying, “I don’t have the luxury of two years of study.” It is about as succinct an expression of the inherent conflict in medical research between risk and careful scientific study as you’ll ever see.
And help him Edwards does. The two operate on Chickering’s mother at Mt. Sinai in secret, with Chickering’s father in the room, unable to watch. Not surprisingly, the surgery does not go well. The tumor does not soften as predicted, and the two surgeons get into bleeding and do damage to Mrs. Chickering’s airway while trying to separate the tumor from surrounding structures. They are also discovered by a janitor, who informs Zinberg, who bursts in a few minutes later demanding to know what the hell is going on. To his credit, when Zinberg sees the situation, he refrains from further scolding and leaps in to help as much as he can. Unfortunately, they can’t save Mrs. Chickering, who dies on the table. Thus ends Chickering’s tenure at Mt. Sinai. He resigns before Zinberg can fire him; not surprisingly he winds up back at the Knick with Thackery, who has actually become slightly less reckless.
This fundamental conflict between careful, slow scientific progress and the need to do something for patients who are suffering now and going to die soon is a theme Gladwell revisits in his article. Of course, most clinical researchers are not a Dr. Thackery or a Dr. Zinberg, who really are archetypes more than anything else. Most physician-scientists and clinical researchers fall somewhere in between these extremes. What seems to bother Gladwell and Dr. DeVita is that over the last three decades the balance in medicine has clearly moved away from the Thackerys and towards the Zinbergs, which leads DeVita to make the same sorts of misguided arguments that I’d discussed being made for right-to-try laws, the Saatchi bill, and the 21st Century Cures Act, all of which seek to remove patient protections in the name of letting Maverick Doctors “innovate” more.
Brave Maverick Oncologists and the wild, wild West of the 1960s
When I referred to Vincent DeVita as a “god” of oncology, I was only exaggerating slightly. If you don’t believe me, go back and read a post I wrote two years ago that uses one of DeVita’s review articles as a jumping off point to discuss how chemotherapy went from a near-fringe idea to being validated as a successful treatment for a number of cancers. It’s a good overview of the history of chemotherapy, a history that DeVita lived right in the middle of and whose success he was very much a part of. Now 80 years old, DeVita uses his book to look back at the history of cancer chemotherapy, and the anecdote that Gladwell chooses to start his article is very telling:
In the fall of 1963, not long after Vincent T. DeVita, Jr., joined the National Cancer Institute as a clinical associate, he and his wife were invited to a co-worker’s party. At the door, one of the institute’s most brilliant researchers, Emil Freireich, presented them with overflowing Martinis. The head of the medical branch, Tom Frei, strode across the room with a lab technician flung over his shoulder, legs kicking and her skirt over her head. DeVita, shocked, tried to hide in a corner. But some time later the N.C.I.’s clinical director, Nathaniel Berlin, frantically waved him over. Freireich, six feet four and built like a lineman, had passed out in the bathtub. Berlin needed help moving him. “Together, we pulled him up, threw his arms over our shoulders, and dragged him out through the party,” DeVita writes, in his memoir, “The Death of Cancer” (Sarah Crichton Books). “Out front, Freireich’s wife, Deanie, sat behind the wheel of their car. We tossed Freireich in the backseat and slammed the door.”
Half a century ago, the N.C.I. was a very different place. It was dingy and underfunded—a fraction of its current size—and home to a raw and unruly medical staff. The orthodoxy of the time was that cancer was a death sentence: the tumor could be treated with surgery or radiation, in order to buy some time, and the patient’s inevitable decline could be eased through medicine, and that was it. At the N.C.I., however, an insurgent group led by Frei and Freireich believed that if cancer drugs were used in extremely large doses, and in multiple combinations and repeated cycles, the cancer could be beaten. “I wasn’t sure if these scientists were maniacs or geniuses,” DeVita writes. But, as he worked with Freireich on the N.C.I.’s childhood-leukemia ward—and saw the fruits of the first experiments using combination chemotherapy—he became a convert.
You get the idea. Back in 1963, men were men, women were women, and the sheep ran scared. Or something. Maybe it was Mad Men, but with oncologists and cancer researchers instead of advertising executives. Or maybe the NCI was the wild, wild West, populated by nothing but Maverick Doctors. As I will discuss, the wild frontier turns out to be a very good metaphor for cancer research as practiced 50 years ago, at least in terms of the attitudes of the physicians at the forefront back then compared to the way things are done now.
Having established early NCI of the early 1960s as the wild West, Maverick doctor bona fides of the era, Gladwell next relates anecdotes from DeVita’s book in which a Maverick doctor shows those cautious, pointy-headed professors how curing cancer is done, starting with one of DeVita’s own accomplishments when he decided to try to replicate Frei and Freirich’s success with childhood leukemia in an adult malignancy. Back in the early 1960s, Hodgkin’s disease, too, was also a virtual death sentence, with very little that doctors could do to save the lives of patients diagnosed with the disease. Over a few beers one night, DeVita and a colleague named Jack Moxley mapped out a protocol based on what Frei and Freireich were doing with leukemia. Because of the ability of cancer cells to mutate and develop resistance under the selective pressure of chemotherapy, they estimated that they needed four drugs, each working through a different mechanism, so that the cells that survived one wave would be killed by the next. They then plotted how often the drugs could be given and how high the doses would need to be. Obviously, the doses needed to be high enough to kill the cancer cells but not so high that the patient died. Ultimately they settled on a regimen called MOMP: three eleven-day rounds of nitrogen mustard, Oncovin (a brand of vincristine), methotrexate, and prednisone, interspersed with ten-day recovery cycles.
This story is the very essence of science-based medicine combined with “maverick-y-ness. Here, two oncology fellows carefully examined the medical literature regarding chemotherapy drugs and what was known about the biology of Hodgkins’ lymphoma at the time and came up with what seemed to be a reasonable combination of drugs. It’s not something that could be done today in the same way, but as I will explain, contrary to what DeVita and Gladwell seem to think, that’s not a bad thing. In the meantime, let’s look at what happened:
“The side effects were almost immediate,” DeVita writes:
The sound of vomiting could be heard along the hallway. Night after night, Moxley and I paced outside the rooms of our patients, fearful of what might happen. Over the weeks that followed, they lost weight and grew listless, and their platelet counts sank lower and lower to dangerous levels.
Then came the surprise. Twelve of the fourteen patients in the initial trial went into remission—and nine stayed there as the months passed. In most cases, the tumors disappeared entirely, something that had never before been seen in the treatment of solid tumors. In the spring of 1965, DeVita went to Philadelphia to present the results to the annual meeting of the American Association for Cancer Research. He stood up before the crowd and ran triumphantly through the data: “ ‘Our patients were, therefore,’ I said, savoring the dramatic conclusion, ‘in complete remission.’ ”What happened? An illustrious cancer expert named David Karnofsky made a narrow point about the appropriateness of the term “complete remission.” After that, nothing: “There were a few perfunctory questions about the severity of the side effects. But that was it.” History had been made in the world of cancer treatment, and no one seemed to care.
Why did DeVita’s work receive such a lukewarm reception? It’s hard to say. It could well have been the natural reticence and skepticism that scientists exercise upon hearing radical new results. It could well have been that the audience thought the data too good to be true. Whatever the reason, Gladwell next discusses the next stage of DeVita’s career, when after finishing his fellowship at the NCI he went to Yale to do another year of residency before coming back to the NCI. A stronger echo of Dr. Chickering’s experience leaving the Knick and taking a position at Mt. Sinai would be hard to imagine:
When his first go-round as a clinical associate at the N.C.I. was up, DeVita took a post as a resident at Yale. At what was supposed to be a world-class hospital, he discovered that the standard of care for many cancers was woefully backward. Freireich had taught DeVita to treat Pseudomonas meningitis in leukemia patients by injecting an antibiotic directly into the spinal column—even though the drug’s label warned against that method of administration. That was the only way, Freireich believed, to get the drug past the blood-brain barrier. At Yale, DeVita writes, “you just didn’t do that kind of thing. As a result, I watched leukemic patients die.” Leukemia patients also sometimes came down with lobar pneumonia. Conventional wisdom held that that ought to be treated with antibiotics. But N.C.I. researchers had figured out that the disease was actually a fungal infection, and had to be treated with a different class of drug. “When I saw this condition in patients with leukemia and pointed it out to the chief of infectious diseases at Yale, he didn’t believe me—even when the lab tests proved my point,” DeVita continues. More patients died. Leukemia patients on chemotherapy needed platelets for blood transfusions. But DeVita’s superiors at Yale insisted there was no evidence that transfusions made a difference, despite the fact that Freireich had already proved that they did. “Ergo, at Yale,” DeVita says, “I watched patients bleed to death.”
Elsewhere, DeVita relates how he had originally wanted to do a fellowship at Yale too but decided to come back to the NCI after a year because of his experiences at Yale.
It’s hard to judge this story without knowing a bit more, but notice how DeVita said that Freirich had taught him to treat Pseudomonas meningitis with intrathecal antibiotics. Had he yet published a convincing clinical study showing that intrathecal antibiotics worked better? I searched for Freireich’s publications on Pseudomonas infections from the 1960s; all I could find was an analysis of 54 episodes of multiple organism sepsis in leukemia patients from 1965, which isn’t applicable to the problem. A search for Freirich’s name and just “meningitis” only revealed this case report from 1968 on Listeria monocytogenes meningitis. In other words, as far as I can ascertain, Freireich had apparently not published his experience with the use of intrathecal antibiotics for meningitis in leukemia patients at the time DeVita was at Yale. Similarly, I was not able to find papers by Freireich on fungal infections before 1968. So why on earth would the doctors at Yale believe DeVita? Why should they have? If it’s not published, then why would they do it? On the other hand, Freireich had published several papers on the effectiveness of transfusions by the late 1960s, one in the New England Journal of Medicine in 1959.
Whether or not he was off base criticizing his colleagues at Yale in the late 1960s, DeVita does note something that I’ve noted myself, as have many others, namely that new ideas are often resisted and that clinical practice doesn’t always change. He noted that he couldn’t do a combination-chemotherapy trial in the US because it went against the grain at the time, necessitating doing it overseas. He also cites the example of Bernie Fisher, who had shown that there was no difference in survival in breast cancer between radical mastectomy and much less invasive breast-conserving surgery followed by radiation therapy, and how he had had difficulty enrolling patients to his studies because of resistance from surgeons.
What DeVita neglects to note is that eventually data did win out, and our practice changed. Indeed, I myself have never even done a radical mastectomy because the procedure had been obsolete years before I did my surgical residency. Heck, my practice has changed radically, in response to clinical trials, just since I first became an attending in 1999. As I like to point out, change in science-based medicine is messy. It often takes more time than we think it should, particularly in retrospect. But eventually we do change practice in response to data and science. At the heart of this change, the question is always: How much new evidence is required before a critical mass of physicians are convinced to change practice? Not all conservatism in medicine is bad. One need only point to the debacle that resulted from the much too rapid adoption of high dose chemotherapy and bone marrow transplantation for advanced breast cancer that became popular in the 1990s, only to be shown to do no good and cause a lot of harm when decent randomized clinical trials were done.
Innovation versus practice guidelines
A second key anecdote from DeVita’s book related by Gladwell involves DeVita’s experience with how a new regimen that he developed was altered as it spread from the NCI to other cancer centers, in this case Memorial Sloan-Kettering Cancer Center (MSKCC). Basically, over the next few years, DeVita and colleagues refined the MOMP regimen, which became MOPP: two full doses of nitrogen mustard and vincristine on the first and the eighth days, and daily doses of procarbazine and prednisone for fourteen days, followed by two weeks of rest. The results of a second trial, published in 1970, showed MOPP to be superior to MOMP.
What puzzled DeVita was how tepid the response was at MSKCC when he presented his work there. Indeed, oncologist after oncologist there told him MOPP “didn’t work.” Why was that? Ironically enough, it was the product of the very same sort of tinkering that DeVita had used seven years earlier to develop MOMP:
Baffled, he asked one of the hospital’s leading oncologists, Barney Clarkson, to explain exactly how he was administering the MOPP protocol. Clarkson answered that he and his colleagues had decided to swap the nitrogen mustard in DeVita’s formula for a drug called thiotepa. This was a compound they had developed in-house at Memorial Sloan Kettering and felt partial to. So MOPP was now TOPP. DeVita writes:
They’d also cut the dose of procarbazine in half, because it made patients nauseous. And they’d reduced the dose of vincristine drastically because of the risk of nerve damage. They’d also added, at a minimum, an extra two weeks between cycles so that patients would have fully recovered from the toxic effects of the prior dose before they got the next. They gave no thought to the fact that the tumor would have been back on its feet by then, too, apparently.
These alterations had not been tested or formally compared with DeVita’s original formula. They were simply what the oncologists at Memorial Sloan Kettering felt made more sense. After an hour, DeVita had had enough:
“Why in God’s name have you done this?” he asked.
A voice piped up from the audience. “Well, Vince, most of our patients come to us on the subway, and we don’t want them to vomit on the way home.”
Here were physicians at one of the world’s greatest cancer hospitals denying their patients a potentially life-saving treatment because their way felt better.
So basically, the doctors at MSKCC had altered the protocol, and the resultant protocol, TOPP, didn’t work. What would have been appropriate, if the oncologists at MSKCC really thought their protocol was an improvement, would have been to do a clinical trial comparing MOPP to TOPP head to head, but they didn’t do that. They just changed DeVita’s protocol as they saw fit and started using it. For them to conclude that TOPP didn’t work, it must have been very obviously different from the results reported by DeVita with MOPP, because there was no control group and no clinical trial. Worse, if DeVita’s account is to be believed, the oncologists at MSKCC didn’t even differentiate their new protocol from DeVita’s original protocol or figure out that the reason that their protocol didn’t work was because of their alterations.
One might think that this sort of experimentation would indicate that perhaps there should be some clinical guidelines that made sure that MOPP, which had been validated as effective in clinical trials, should be administered the same way, but that’s exactly the opposite of what DeVita argues, according to Gladwell:
But here “The Death of Cancer” takes an unexpected turn. DeVita doesn’t think his experience with the stubborn physicians at Memorial Sloan Kettering or at Yale justifies greater standardization. He is wary of too many scripts and guidelines. What made the extraordinary progress against cancer at the N.C.I. during the nineteen-sixties and seventies possible, in his view, was the absence of rules.
And:
Clinical progress against a disease as wily and dimly understood as cancer, DeVita argues, happens when doctors have the freedom to try unorthodox things—and he worries that we have lost sight of that fact.
Where have we heard these arguments before? Oh, yes. I remember. They’re the same arguments made by proponents of the Saatchi Bill and the misguided 21st Century Cures Act. The central idea behind all of these policy ideas is that we somehow have to “free” doctors and researchers to “innovate,” rather than “shackling” them. The impetus for these ideas is, in essence, worshiping at the altar of the cult of the Brave Maverick Doctor. It is the Great Man (or Woman) theory of the history of medicine, in which breakthroughs come not so much because of the gradual accretion of knowledge, with each new scientific finding building on what has been discovered before, but because of singular individuals with the vision and the bravery to see what needs to be done and the cleverness, intelligence, and will to do it.
DeVita vs the FDA
Gladwell notes that the angriest part of DeVita’s book is his chapter about the FDA, where he argues that the FDA has somehow fundamentally misunderstood innovation. I rather suspect a lot of DeVita’s hostility comes from two experiences he had in his life. First, he describes a prolonged battle to save his friend Lee, who developed advanced prostate cancer. DeVita kept pushing to get him into clinical trial after clinical trial, to get experimental therapies off protocol, and basically to try anything that could be tried, ending when he couldn’t get his friend an experimental drug called abiraterone. His friend died He later learned that abiraterone was so effective that the clinical trial was halted early and now clearly believes that he could have saved him, even though there is no cure for advanced prostate cancer. (Abiraterone significantly prolongs life, but is not a cure.) Even so, abiraterone was no cure. Another incident is that DeVita, ironically enough, was the father of the Ted DeVita, the “boy in the bubble,” who developed aplastic anemia and lived well over eight years in a plastic bubble before succumbing.
Specifically, he objects to the FDA’s mandate to require that all new approved drugs be safe and efficacious, pointing out that this “gatekeeping” function of the FDA can hinder progress. I’ll have to wait to read the book to see if DeVita’s argument is more compelling than how Gladwell represents it, but I was underwhelmed, as not a single example of how “progress” had been hindered was provided, only hypothetical examples. In one, he suggests that cancer is like a door with three locks, each with a different key. If a drug “opens the first lock,” it would be a breakthrough but wouldn’t cure the cancer by itself. So DeVita asks:
So how do you get it through a trial that requires proof of efficacy—especially if you don’t yet know what the right keys for the two remaining locks are? Since cancer comes in a dizzying variety of types and subtypes, each with its own molecular profile, we want researchers to be free to experiment with different combinations of keys.
The problem with this analogy is that it is disappointingly simplistic given who is making it and that the time to work out the preliminary answer to this question is in preclinical research leading to the development of this drug and others, not in human beings. Moroever, as represented by Gladwell, this argument completely ignores the incredible genetic heterogeneity of even a single cancer, where different cells, even in the same tumor, might have different combinations of these locks. He also criticizes the FDA for approving drugs for very specific indications, including specific cancers and even specific stages of cancers, complaining, “The vital insight gained by using an approved drug in a different way for a different tumor has been lost.” No, it has not. In this age of precision medicine based on genomics, if anything, we’re becoming more open to trying drugs designed for one tumor in another tumor based on the genetic abnormality it targets rather than the tissue of origin of the tumor. The FDA is struggling, as we all are, with the question of how to target therapy to the individual characteristics of the tumor. New forms of clinical trials are being tested. New regulatory frameworks are being developed.
To his credit, Gladwell points out exactly what’s wrong with DeVita’s argument for more freedom to tinker, specifically the paradox at the heart of it. First, he notes that the breakthroughs at the NCI in the 1960s and 1970s were the product of a freewheeling intellectual climate and a relative lack of rules over what could and could not be done in clinical trials. Indeed, it’s quite true that no one could do now what DeVita did 52 years ago. At the same time, it was that very same climate that allowed the oncologists at MSKCC muck up DeVita’s effective chemotherapy regimen by turning MOPP into TOPP. The problem with such a freewheeling atmosphere without rules is that, for it to be a net benefit, there have to be more doctors like Emil Freireich and Vincent DeVita than there are like Barney Clarkson, as Gladwell notes. Personally, having been in medicine in one form or another for 30 years now, I am not nearly so confident that there aren’t a lot more Barney Clarksons than Vincent DeVitas. In fact, I’m quite sure that there are and that, contrary to DeVita’s claims that an extra 100,000 more patients a year could be cured if we just used all the wonderful drugs out there to their fullest potential, opening medical practice and research to the sort of “innovation” DeVita proposes would end up harming far more patients than it would ever help.
Let’s just put it this way. By DeVita’s definition, Stanislaw Burzynski is “innovating” with his “make it up as you go along” form of “personalized gene-targeted” cancer therapy combined with his antineoplastons. After all, “innovation” is very difficult to identify, except in retrospect, after we know what works and what doesn’t, who is a Stanislaw Burzynski-style maverick and who is a Vincent DeVita-style maverick.
The problem with mavericks and nostalgia
‘Cause the good ole days weren’t
Always good
And tomorrow ain’t as bad as it seems
DeVita’s complaints about medicine are not uncommon. I tend to hear complaints like his from (mostly) an older generation of physicians who came of age in terms of their medical career during times when physician autonomy was perceived to be much closer to absolute and constraints on doing research less onerous, in other words, in a more freewheeling “wild West” sort of atmosphere. Given that, I can’t help but think that there is more than a little nostalgia, a pining for the “good old days,” in DeVita’s book. I also can’t help but wonder if Gladwell was rather selective in his quoting of DeVita, given that in an NPR interview just one month ago promoting his book, DeVita said very little that was so critical of the state of cancer research.
Be that as it may, I tend to view new fields of medical research as being rather like the American frontier. The first ones in are the hardiest and bravest, the ones willing to take the most risk, such as trappers and mountain men. They clear the way for the next wave, and as new arrivals keep coming, civilization intrudes. There are more and more laws and rules, and there is no longer absolute freedom. Eventually, what was once frontier is now little different from the states where all the settlers came from, and the original trailblazers have either moved on or struggle to fit in. Cancer research is rather like that. Back in its “wild West” period, because so little was known about cancer and so few effective treatments existed outside of surgery for certain specific cancers, there was an “anything goes” culture because, or so it was perceived, there was much to gain and very little to lose by trying almost anything. So men like DeVita (and, yes, unfortunately is was almost all men back then) did. Also, the less that’s known, the more variability in care is acceptable, because we don’t know what the best existing treatment is. The more we learn, the greater the risk in practicing outside of evidence-based guidelines because doing so becomes more likely to harm than help.
We are all products of our time and experiences, and DeVita is no different. He became a cancer researcher in a specific time and place, and his life experiences, particularly with his son with aplastic anemia and his friend with prostate cancer shaped his views. Think of it this way: DeVita, as brilliant as he is and as deserving as he is of all the respect he gets, was nonetheless very fortunate very early in his career. After all, his first attempt at innovation through tinkering happened to be a smashing success. There was no guarantee at the time that this would be the case. Indeed, it’s not hard to imagine an alternative history, in which his first attempt at multimodality chemotherapy was so toxic that it killed most of his patients before their cancers could or was simply ineffective and toxic. Would DeVita view giving physicians unfettered freedom to “tinker” so favorably if that had been the case? After all, in other hands, such tinkering resulted in an ineffective treatment combination.
One thing I like about The Knick is that it shows that one maverick can easily produce both outcomes: disaster and greatness. In other words, it’s a mistake to separate mavericks into Freireich-style mavericks and Clarkson-style mavericks. Any single maverick, for any given bit of “tinkering,” can produce Freireich or DeVita results or he can produce Clarkson-style results. Indeed, when Brave Maverick Surgeon John Thackery does his “tinkering,” sometimes, he’s successful, as when he successfully separates a pair of conjoined twins this season. More often, Thackery fails miserably. Two of the more dramatic failures occurred late in the first season when Thackery outright killed a girl transfusing her with his own blood based on his incorrect hypothesis of what determined different blood types and in the second season when, while trying to treat a man’s addiction by ablating part of his brain with an electrical probe, he inadvertently damaged part of the brain that resulted in a locked in patient, about as horrible an outcome as can be imagined. (If you don’t know what locked in syndrome is, read this or watch The Diving Bell and the Butterfly. It’s arguably a fate worse than death.) This season, when Chickering, following the lead of his mentor, tries an experimental treatment on his mother, disaster ensues. The converse can also happen, as in the first season when Dr. Zinberg develops the “illuminating intrascope,” which allows doctors to look inside their patients without making large incisions. (Basically, it was a precursor to what we use today as the laparoscope.) This conflict appears poised to play itself out in the season finale tonight, as the synopsis includes this: “Thackery eschews Zinberg’s (Michael Nathanson) advice at Mt. Sinai and opts for a dramatic, and risky, alternative course of action.”
Same as it ever was.
Unlike 50 (or 115) years ago, medicine today is, for better or worse, largely a “team sport.” This is particularly true when it comes to serious diseases like cancer. For instance, in my specialty, breast cancer surgery, it’s uncommon that I am the only physician involved in the care of my patients with breast disease. It happens for patients undergoing a biopsy and for patients with ductal carcinoma in situ whose tumors are hormone receptor negative and who are thus not going to benefit from estrogen-blocking therapy. Even in both of these cases, at the very least a pathologist is also involved. The care of the rest of my patients involves a combination of surgery, radiation oncology, and medical oncology.
The collaborative nature of cancer care today can be frustrating to some doctors. In addition, there is a certain type of personality that views evidence-based guidelines as “being told what to do.” It’s not hard to find these doctors; indeed, just peruse the feed for Kevin, MD, and it won’t take more than a few days for you see them, and if you peruse the AAPS Twitter feed, you’ll see them in spades. Truly, the appeal of the cult of the Brave Maverick Doctor is strong. It’s just disappointing to see a physician as eminent as Vincent DeVita worshiping at the altar of the cult of the Brave Maverick Doctor.
Few physicians are as brilliant as Dr. DeVita or Dr. Freireich, and even brilliant maverick doctors “tinkering” the way DeVita did tend to be wrong far more often than they are correct. That’s why, as The Knick puts it, there are rules. Reasonable people can disagree over how strict those rules need to be, but there have to be rules.
from ScienceBlogs http://ift.tt/1PaRRBM
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