The Same Old Song: How Little Has Changed In Oncology

By

Leonard Zwelling

When it comes to clinical research in oncology, I am pretty well out of it. It’s been twelve years since I oversaw any piece of research administration and 15 since I was running the infrastructure for clinical research at Anderson. My last RO1 ended about 18 years ago. My data are old. My perspectives are dated.

Thus, it is always amusing to dip my toe back in the water of academic oncology by going to a meeting or reading a few papers. I keep up with the New England Journal of Medicine and Science, but that is a mere fraction of what I used to read. I know nothing about the new, gene-targeted agents or the immune modulators or drugs that target kinases and transcription factors. So when I go to a meeting, I am bound to learn something.

The week of November 13, I accompanied the BW to Tokyo for the annual meeting of the Connective Tissue Oncology Society (CTOS). It’s a gathering of a few hundred academic physicians and researchers who study the rarer tumors that plague humanity, sarcomas. Obviously, the BW is a major player here as she and her colleagues used the basic science of Josh Fidler who discovered that liposomal-mediated immunomodulation by macrophage stimulating agents can alter the natural history of a cancer in mice that behaved like human osteosarcoma, a bone malignancy that mostly, but not only, targets adolescents. The basic science led to a series of successful trials and the drug’s approval all over the world. One of Genie’s former patients is now a faculty member at a major university studying the disease that almost killed him.

Here are the takeaways from my sitting through an afternoon of excellent talks about the treatment of these tumors.

First, the number of new agents to treat this disease group is staggering and runs the gamut from antibodies to small molecules that target enzymes and factors controlling gene expression. Even cellular therapy may have a role in the treatment of sarcomas in the future.

Second, most of the clinical studies of new drugs do not confirm the mechanism by which these drugs are thought to be working when they work and the success rate is not trivial. Some responses are truly amazing. Why the magic works is another matter and validating tumor targets of new drugs ought to be a more prominent part of novel clinical trials.

Third, this is a very heterogeneous set of diseases and much rarer than breast or colon cancer. Making generalizations about the efficacy or safety of these drugs in this setting is not easy as sarcomas may have to be grouped (lumping) when splitting is the way the new thinking is going, that is each patient-drug combination may be an N of 1.

Fourth, the cost of this research is very high as the drugs are pricey and the acquisition of the needed data for regulatory approval is also expensive. I suspect part of the reason more mechanistic studies are not done is that their cost is high, unbillable and of limited interest to drug company sponsors as mechanistic studies may not advance a drug’s chance for FDA approval.

Fifth, the alteration of the natural history of the diseases by the drugs is incremental at best.

Why is this all fascinating?

Because the questions asked and the results sought are the same as they were forty years ago. The measurement tools are more sophisticated, and the number of agents more numerous, but the basic questions remain.

What works and what does it mean “to work?”

How does it work?

If it works do we care how it works?

Who is going to pay for all of this research when there are still many millions of Americans without access to basic health care?

Works still means tumor shrinkage, increased time to recurrence, and prolonged survival. Many of the new drugs seem to be doing this.

The mechanisms of action are about as well known as those of vincristine and cyclophosphamide. We think we know what they do chemically and in cultured cells, but is that what they do to kill the tumor in a human? Who knows?

If you can get 80+% survival rate in a disease like we can do with acute lymphoblastic leukemia in kids treated with chemotherapy, does anyone really care how the drugs work?

But the one that overwhelmed me is the last question. The price of this research is very large. While the research goes on all over the world, it is in the U.S. that the drug companies make the big money that pays for all of this research. That’s one of the reasons that drug prices are so high here and less so in other countries where prices are controlled and access to newer agents is not as ready as it is here.

As novel as the clinical science that I saw was, the questions are the same ones that were being asked forty years ago when I went to my first ASCO meeting.

The more things change, the more they stay the same. And the band played on.

To a relative outsider like me, the progress appears great. But to the old-timer in me, it seems that not much has changed in the sphere of clinical oncology research even as the sophistication of the questions and the tools to answer them deepen.

Leonard Zwelling