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Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Wednesday, August 24, 2011
How Eras End

I am a big fan of what used to be called "Books on Tape." Anyone other than me still remember when data was stored on tape? Anyways, one of my favorite ways to fill the half hour it takes me to get to work involves listening to lectures in the "Great Courses" series. These allow me to get caught up on all I missed as a pre-med at the University of Wisconsin. Lately I've been listening to a course on medieval philosophy.

 

Medieval philosophy peaked, I learned, with three great philosophers: Thomas Aquinas, John Duns Scotus, and William of Ockham. Each, in their own way, wrestled with the challenge of harmonizing faith and reason.  

 

Aquinas, in particular, felt that he had proven, through coolly rational Aristotelian logic, the existence of God. The Catholic Church subsequently declared him a saint for his contributions to theological science, which wasn't bad for an academic -- sort of the 14th century equivalent of a Nobel Prize, I guess.

 

This great synthesis collapsed almost immediately (or immediately in Middle Ages terms -- it took a few decades). William of Ockham (or Occam) came along and, with rigorous logic, demolished much of the rationale underpinning the work of Aquinas. And though Ockham was a firm believer, he was convinced that faith and reason were essentially irreconcilable. You could, and should, believe in God, but your belief would ultimately, necessarily, be grounded in faith rather than in reason.

 

For someone who died the year the Black Death broke out (1348), Ockham is a curiously modern figure. If not, like Aquinas, a saint of the church, he became a saint of modern science. We remember him today primarily because of his famous "razor": “Entia non sunt multiplicanda praeter necessitatem.” As rephrased by Newton, “We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances.” Simple is better.

 

Ptolemy explained celestial mechanics, but Copernicus's explanation was far simpler, requiring fewer kludges to make it work -- a classic example of Ockham's razor at work.

 

Max Planck settled on quantum theory, the opening shot in modern physics revolution, because it was the simplest explanation for the facts, not because he liked the answer (apparently he didn't). More recently, Ockham's razor has even had a formal mathematical proof developed in the information sciences by the German computational scientist Marcus Hutter. The Razor still cuts.

 

What, I hear you saying, does any of this obscure medieval philosophy stuff have to do with oncology? Just this: after dominating academic discourse for over a century, the university elites dropped the attempt to reconcile faith and reason. They dropped it not because they ran out of things to philosophize about, but because they no longer believed in the intellectual agenda itself. It suddenly ceased to be an interesting question. They no longer thought that they could reach a solution to the problem with the tools available. The best minds moved on.

 

I have already lived through one such moment in the history of oncology: the crisis of faith surrounding chemotherapy. I trained and grew to intellectual maturity in an era when the academic agenda was dominated, not just by the tool kit of chemotherapy, but also by a belief in the ability of chemotherapy to solve the problem of cancer.

 

Academicians seriously believed (a belief as fervent as that of any medieval theologian) that the solution to cancer was more chemotherapy: either more drugs (with the creation of ridiculously long acronyms signifying increasingly complex drug combinations) or more drug (dose intensity, dose density, high dose chemotherapy with autologous stem cell transplantation).

 

I vividly remember attending a conference where some hapless junior faculty member was discussing a new agent's Phase II effects on a patient with refractory breast cancer. One of the grand high mucky-mucks of transplantation got up and shouted (shouted!) out from the back row, "Why don't you just hold a gun to her head and shoot her?" The implication being, of course, that salvation (cure) lay in the use of high dose chemotherapy, if only you believed in the healing power of transplants, and damnation lay in the pointless attempt to find new agents when the existing ones were not being used in high enough dosage.

 

And then, by the end of the 1990's, that was all past. I have spoken to no one in recent years who believes that adding a new chemotherapy drug to the mix, or a higher dose of that drug, will cure any metastatic cancer. I repeat: no one, for any metastatic cancer.

 

And this isn't because we ran out of new drugs. In my own field, breast cancer, there have been a profusion of interesting and useful new chemotherapeutic agents in the past 15 years. We didn't run out of new chemotherapy drugs to test the hypothesis that new chemotherapy drugs will cure cancer. Instead, we suffered a crisis of faith. As a community we ceased to believe in even the possibility that chemotherapeutics might cure cancer.

 

I wonder if we are about to encounter a similar crisis of faith, this time involving targeted therapy. Just as we had early dramatic successes with chemotherapy (childhood leukemia, testicular cancer) that held out the hope that universal cures for cancer were at hand, we saw similar striking successes with targeted therapies (trastuzumab, imatinib).

 

Those successes are still rolling out with some regularity, as this year's BRAF story suggests. They won't go away, of course, any more than chemotherapy will disappear, or (for that matter) Catholic churches will stop being named after Aquinas.

 

But I wonder if (or fear that) targeted therapy is at its Thomas Aquinas peak, with nemesis (in the guise of genomics and its relatives) waiting patiently in the wings. We have picked a lot of the low hanging fruit. The genomic landscape that I see for most "smart” cancers is one of enormous complexity, not amenable to simple fixes with a single tyrosine kinase inhibitor, or even a few in combination. I don't think we will lose faith in the utility of individual kinase inhibitors, but we may soon question their ability to deliver "The Cure." just as we did with chemotherapy.

 

And I remember my favorite line from the movie Jaws: "I think we need a bigger boat."

 

The good news, of course, is that there is a whole flotilla of boats headed this way. So I remain an optimist about cancer (I retain my faith in its eventual curability) even as I become more skeptical that we have all the right tools. Just call me George of Ockham.

 

 

About the Author

George W. Sledge, Jr., MD
GEORGE W. SLEDGE, JR., MD, is Chief of Oncology at Stanford University. His OT writing was recognized with an APEX Award for Publication Excellence in the category of “Regular Departments & Columns.”