Tuesday, August 4, 2009

advice about clinical trials

I received another pearl of wisdom from Dr. Bill Keezer that deserves to be shared more widely, so I'm reproducing his email here, with minor edits.


I understand your concerns over therapies for cancer, and Dr. Bajaj sounds less warm or sympathetic than one would like in a doctor. From my own perspective, and I have put some thought and reading into cancer mechanisms over the years, the idea of individual therapies based on genetics is pseudo-science. I fully agree that many cancers have different etiologies, but I suspect that the underlying mechanisms and locations of genetic damage are fewer than the number of distinct cancers. Also, once the damage is done, it may not be reversible, but rather one is still in the problem of dealing with the results, not the lesion(s) themselves.

Some reading I did several years ago indicated that there are multiple pre-disposing factors to cancer and multiple steps to get there. There is also the matter of when and where the factors get expressed. Childhood tumors are far more aggressive than adult tumors, which seems to go along with the fact that children are growing and developing--it potentiates the cancer growth and development. The same underlying mechanism in one tissue with its own internal growth and metabolism controls will have different expression than in another tissue.

The same factors in different tissues seem to cause different progressions. The vulnerable links in the cancer will come at different points in its overall metabolism. In fact, rather than deal with the genetics, which sounds so wonderful (and may simply be the result of trying to justify genetic research), it might be more profitable to study the differences among cancers from different tissues and different types of cancer from the same tissue. There has to have been some of this going on, for there to be as many different chemotherapies as there are, and for drugs to have been developed that have fewer side effects.

At one time, chemotherapy was very crude. One administered a cytotoxin, and because the tumor was growing faster than normal cells, it would preferentially be killed. However, the drugs were so toxic that the patient also got sick from normal cell damage. Today, my mother-in-law is taking a chemotherapeutic, and she never did have major side effects except the loss of hair. The drugs are becoming more specific. That is why Avastin is for breast cancer and Temodar is for GBM.

One of the things that I still remember from pathology, is that tumors have stages, and these are not just clinical stages, they are cytological stages. As the tumor becomes more aggressive, it becomes more de-differentiated. Although, that is not the best term; rather, it becomes less distinct as a tissue and more amorphous. The cells lose their particular histological character, and become more and more a blob with a nucleus. It is rather like the control mechanisms are damaged or destroyed. Some of those are genetic in the sense of specific loci on the chromosome, but some may be more general, such as the alteration of the portion of the chromosome called the telomere, which seems to be tied into cellular longevity, and is altered irreversibly in immortal cell lines. If such is the case with cancers, then a genetic treatment is not in the cards.

You should have all the questions in the world for your mom's regular oncologist. You and your dad continue to act as ideally as I can imagine in handling everything on your plates. As for the article on clinical trials, there is a lot of peripheral stuff around them, and a lot of it is forced by a combination of government regulation, scientific validity, and fear of torts. I don't necessarily agree with the undertone that many cures or better results are being lost due to lack of trials. There are probably more lives lost due to excessive requirements of efficacy and safety by the FDA. Plus, whether we like to admit it or not, once a drug is generally sold, the entire population becomes a large-scale clinical trial, albeit uncontrolled and unmonitored in detail. In the case of cancer patients, to be able to take a new drug, perhaps less tested than treatments for chronic disease, could literally be a life-saver or extender. With the death and illness risk of cancer, there can rationally be a higher risk factor in taking drugs, with the proviso that the patient is aware of the more limited testing.

The one doctor trying the reverse of the standard protocol is definitely of interest to me. The rationale sounds good, and the results may come faster. In some cases, a full-fledged clinical trial may not be justified, but even anecdotal evidence can foster further interest and study. Though the results would not be applicable directly without further clinical trials, tissue culture studies would be a great way to do research, and I suspect this is where the drug companies are finding new drugs. It would be analogous to the search for new antibiotics, first screening on bacterial cultures, then tests in animals, finally tests in humans.

It has been very heart-warming to read that your mom is showing mental improvement and a return of physical strength. There is also the underlying pathos of knowing it is limited in time. And so you build up strength during the good times for when they will no longer be, and retain the good memories for when that is all you will have.

On a different note, I have returned to reading Water, and find you and I think very much alike in the main structures, but with different details. As I said earlier, I will write notes that we can discuss when you have the time and energy for it.

In the meantime, my thoughts and prayers are with all of you.



Thanks, Bill, for this very informative email, which will be useful to more than just our own family.

I should note that, although Dr. Bajaj was direct in his answers, he was polite but not cold. Besides, if it's a choice between warm and overly optimistic versus cold and truthful, I'll pick the latter any day. Style and tone aren't as important as substance-- a value I know you share. Fortunately, Dr. Bajaj didn't force me to make such a choice. He was a pro, and I appreciated his candor.

It is indeed painful to know that, no matter what improvements Mom experiences, they'll eventually fade away. It doesn't seem fair, does it? I'm reminded of the poor patients in the movie "Awakenings," or of Charly in the short story "Flowers for Algernon." Both are stories about people in dire conditions who experience temporary improvement, then inexorably slide back into oblivion.*

Of course, "eventually fading away" is what we're all destined do. Buddhists are fond of remarking, "Look around you at the people in this room. In a hundred years, none of them will be alive, including you." Impermanence is a trivial yet powerful fact of physical existence, and making sense of death is one of the most important human tasks-- a task that some of us spend our lives running away from. For me, I have no trouble facing the prospect of my own eventual decease, but knowing that this will happen to those I love-- very likely in ways that will seem cruel or miserable-- is a phantom with which I wrestle constantly, especially these days as I witness my mother's decline.

Thank you again for your many insights, and for the care that prompted you to offer them.

*"Awakenings" is a fictional story, but is based on the life and accomplishments of Dr. Oliver Sacks, whose The Man Who Mistook His Wife for a Hat is one of my favorite works of medical nonfiction.


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