The Truth in Small Doses: Interview with Clifton Leaf (Part 1 of 2)

I found a lot to like and agree with in The Truth in Small Doses: Why We’re Losing the War on Cancer — and How to Win It by Clifton Leaf, published recently. It grew out of a 2004 article in Fortune in which Leaf described poor results from cancer research and said that cancer researchers work under a system that “rewards academic achievement and publication over all else” — in particular, over “genuine breakthroughs.” I did not agree, however, with his recommendations for improvement, which seemed to reflect the same thinking that got us here. It reminded me of President Obama putting in charge of fixing the economy the people who messed it up. However, Leaf had spent a lot of time on the book, and obviously cared deeply, and had freedom of speech (he doesn’t have to worry about offending anyone, as far as I can tell) so I wondered how he would defend his point of view.

Here is Part 1 of an interview in which Leaf answered written questions.

SR Let me begin by saying I think the part of the book that describes the problem – little progress in reducing cancer – is excellent. You do a good job of contrasting the amount of time and money spent with progress actually made and pointing out that the system seems designed to produce papers rather than progress. What I found puzzling is the part about how to do  better. That’s what I want to ask you about.

In the Acknowledgements, you say Andy Grove said “a few perfect words” that helped shape your thesis. What were those words?

CL “It’s like a Greek tragedy. Everybody plays his individual part to perfection, everybody does what’s right by his own life, and the total just doesn’t work.” Andy had come to a meeting at Fortune, mostly just to chat. I can’t remember what the main topic of conversation was, but when I asked him a question about progress in the war on cancer, he said the above. (I quote this in the 2004 piece I wrote for Fortune.)

SR You praise Michael Sporn. His great contribution, you say, is an emphasis on prevention.  I have a hard time seeing this as much of a contribution. The notion that “an ounce of prevention is worth a pound of cure” is ancient. What progress has Sporn made in the prevention of anything?

CL Would it be alright, Seth, if before I answer the question, I bring us back to what I said in the book? Because I think the point I was trying to make — successfully or not (and I’m guessing you would conclude “not” here) — is more nuanced than “an ounce of prevention is worth a pound of cure.”

Here’s what I see as the key passage regarding Dr. Sporn (pgs. 133-135):

For all his contributions to biology, biochemistry, and pharmacology, though, Sporn is still better known for something else. Rather than any one molecular discovery, it is an idea. The notion is so straightforward—so damned obvious, really—that it is easy to forget how revolutionary it was when he first proposed it in the mid-1970s: cancer, Sporn contended, could (and should) be chemically stopped, slowed, or reversed in its earliest preinvasive stages.

That was it. That was the whole radical idea.

Sporn was not the first to propose such an idea. Lee Wattenberg at the University of Minnesota had suggested the strategy in 1966 to little response. But Sporn refined it, pushed it, and branded it: To distinguish such intervention from the standard form of cancer treatment, chemotherapy—a therapy that sadly comes too late for roughly a third of patients to be therapeutic—he coined the term chemoprevention in 1976.

The name stuck.

On first reading, the concept might seem no more than a truism. But to grasp the importance of chemoprevention, one has first to dislodge the mind-set that has long reigned over the field of oncology: that cancer is a disease state. “One has cancer or one doesn’t.” Such a view, indeed, is central to the current practice of cancer medicine: oncologists today discover the event of cancer in a patient and respond—typically, quite urgently. This thinking is shared by patients, the FDA, drug developers, and health insurers (who decide what to pay for). This is the default view of cancer.

And, to Sporn, it is dead wrong. Cancer is not an event or a “state” of any kind. The disease does not suddenly come into being with a discovered lump on the mammogram. It does not begin with the microscopic lesion found on the chest X-ray. Nor when the physician lowers his or her voice and tells the patient, “I’m sorry. The pathology report came back positive. . . . You have cancer.”

Nor does the disease begin, says Sporn, when the medical textbooks say it does: when the first neoplastic cell breaks through the “basement membrane,” the meshwork layers of collagen and other proteins that separate compartments of bodily tissue. In such traditional thinking, it matters little whether a cell, or population of cells, has become immortalized through mutation. Or how irregular or jumbled the group might look under the microscope. Or how otherwise disturbed their genomes are. As long as none of the clones have breached the basement membrane, the pathology is not (yet) considered “cancer.”

For more than a century, this barrier has been the semantic line that separates the fearsome “invader” from the merely “abnormal.” It is the Rubicon of cancer diagnosis. From the standpoint of disease mechanics, the rationale is easy to understand, because just beyond this fibrous gateway are fast-moving channels (the blood and lymphatic vessels) that can conceivably transport a predatory cell, or cells, to any terrain in the body. Busting through the basement is therefore a seeming leap past the point of no return, a signal that a local disturbance is potentially emerging into a disseminating mob.*

But while invasion may define so-called clinical cancer for legions of first-year medical students, it is by no means the start of the pathology. Cancer is not any one act; it is a process. It begins with the first hints of subversion in the normal differentiation of a cell—with the first disruption of communication between that cell and its immediate environment. There is, perhaps, no precise moment of conception in this regard, no universally accepted beginning—which makes delineating the process that much harder. But most, if not all, types of “cancer” have their own somewhat recognizable stages of evolution along the route to clinically apparent disease.

“Saying it’s not cancer until the cells are through the basement membrane,” says Sporn, “is like saying the barn isn’t on fire until there are bright red flames coming out of the roof. It’s absolute nonsense!”

(Sorry for that long excerpt.) I think that Dr. Sporn’s greatest contribution was to reframe cancer as a continually evolving, dynamic process — carcinogenesis — rather than an event or state of being. And it was one that, conceivably at least, we could interrupt — and interrupt earlier than at the point at which it was clinically manifested. This was distinct from early detection, which, while effective to some extent and in some cancers, was both detecting cancers too late and “catching” many lesions that weren’t likely to develop any further (or didn’t really exist to begin with), adding to the already-great cancer burden.

There was a potential, said Sporn, to intervene in a way that might stop developing cancers in their tracks, and yet would not necessarily have to add to the burden of cancer overtreatment.

As I spend most of Chapter 7 discussing, there are enormous barriers to pulling this of—and I did my best to lay out the challenges. But I do believe that this is the way to go in the end.

SR You praise Kathy Giusti for her effect on multiple myeloma research. I couldn’t find the part where that research (“a worthy model for cancer research that can serve as a guidepost for the future . . . that teaches everything there is to teach about the power of collaborative science”, p. 260) came up with something useful.

CL Seth, sorry this again may be me not being very clear in my writing. I apologize for that. But the lines you cite actually are intended to set up the Burkitt story in the following chapter. It was Burkitt’s effort against the mysterious African lymphoma, that remains, in my view, “a worthy model for cancer research…”

SR You praise Burkitt’s epidemiology. How did that epidemiology help find out that Burkitt’s lymphoma responds to certain drugs? I couldn’t see a connection.

CL Good question. I think Burkitt’s very old-fashioned epidemiological investigation identified a widespread, terrible cancer that had been seen many times, but not noticed for what it was. It helped narrow down who was getting this cancer and—at least in a broad, geographical sense—why. But it wasn’t epidemiology that helped discover that this lymphoma was responsive to certain drugs—that was trial and error. As with the case of Farber and ALL [acute lymphocytic leukemia], many today would blanch at the primitive experimental protocols that tested these toxic drugs in children. But with an extraordinarily aggressive tumor that was killing these kids in weeks, Burkitt felt he had to try something. Again, that’s not epidemiology, but it is an understanding of the urgency of this disease that we can, perhaps, learn from.

[End of Part 1 of 2]

3 Responses to “The Truth in Small Doses: Interview with Clifton Leaf (Part 1 of 2)”

  1. Mark Says:

    Seth, thanks! This is wonderful. And you’ve just sold one copy of this book. That said, and I’m not criticizing your reading, but I totally agree with this blurb regarding Sporn. Of course, this is out of the greater context of the book, as well, so maybe I’ll be similarly concerned when I read it (I take the view that most of the preventive epidemiology stuff is pretty much bunk).

  2. RIen Says:

    Nicolas Taleb has something to say about the medical system as well in his most recent book “Antifragility”. In short, he thinks that the current system does not do enough experimentation and tries to much to design a solution. This makes it open to downside (failure) but closes it to upside (unexpected discoveries).

    Seth: My view is the current system makes science into a job. Jobs demand steady results. There can be no taking chances, no long periods of failure. But good science — in contrast to assembly line science — demands exactly that. That is a blend of what Taleb and Leaf say.

  3. dearieme Says:

    Somewhere on the web I saw words to the effect of “Cancer is a thousand diseases with a common symptom.” I wish people would repeat that rather than the ludicrous “The War on Cancer”.

    “Jobs demand steady results. There can be no taking chances, no long periods of failure.” Yes, but why? Who imported this daft mindset into science? After all it’s not the mindset that dominates, for example, oil exploration, where periods of failure are accepted as part of the the cost of big successes.

    Seth: People who aren’t scientists asked for it and scientists agreed. Inherent in the notion of job is trade with people with other jobs. People with other jobs (e.g., legislators, parents, journalists, etc.) give scientists money, attention, and so on and want something in return. Such as visible progress. Scientists themselves don’t point out how deeply science is screwed up by emphasis on short-term progress (Stockholm Syndrome?), so it is unsurprising that outsiders don’t see it.